Role of mitochondria in nuclear DNA damage response
Review Article
Genome Instability & Disease 3, 285–294 (2022)
Abstract
DNA damage response (DDR) is an intracellular pathway that senses and repairs damaged DNA. Proper regulation of this pathway is essential for maintaining genome stability and promoting cell survival. These repair mechanisms are regulated by multiple nuclear DNA damage repair enzymes, which can scan the DNA for problems and restore the DNA double helix structure. In addition to DDR-involved proteins located in cell nuclei, mitochondrial molecular machinery also coordinate this role; the mitochondria sense fluctuations in specific DNA damage signaling and subsequently activate the effector molecules and appropriate pathway. In this review, we summarized the latest scientific literature regarding molecular mechanisms of mitochondria-mediated stress responses in DNA damage signaling. Additionally, we have described future directions necessary for a comprehensive understanding of mitochondria-DDR signaling networks.
Introduction
Cells are constantly disturbed by exogenous and endogenous stressors that can lead to DNA damage, which triggers the DDR and subsequently activates numerous DNA repair pathways (Friedberg, 2008; Ray Chaudhuri & Nussenzweig, 2017). When DNA is damaged, the site of damage is identified, the damaged base nucleotide is removed, the damaged site is processed to accept new bases, where new nucleotide complements are synthesized and generated, and the DNA double helix is rebuilt (Jackson & Bartek, 2009). The DNA repair process involves multiple pathways. For different types of DNA damage, the cell activates corresponding repair mechanisms to ensure genome stability: single-strand damage that is too long and causes twisting of the DNA double helix structure is principally repaired by activating nucleotide excision repair (NER) (Marteijn et al., 2014); base isomerization caused by nucleotide deamination, oxidation, or methylation is principally repaired by base excision repair (BER) (Wallace, 2014); twisting of double-stranded DNA helix caused by non-Watson–Crick base pairing is principally repaired by mismatch repair (MMR) (Jiricny, 2013; Li, 2008). Homologous recombination (HR) and non-homologous end joining (NHEJ) are mainly used to repair DNA double-strand breaks (DSB) that may lead to chromosomal aberrations (Sonoda et al., 2006). In fact, there is crosstalk between these pathways, and certain proteins not intrinsic to the DDR pathway can directly or indirectly affect DNA repair. Moreover, with the deepening of the understanding of subcellular structures in life sciences, the general consensus is that extranuclear subcellular structures (such as mitochondria) may participate in the DDR process by exchanging materials and information with cell nuclei (Canto et al., 2015; Fang et al., 2016).
The process of DNA repair involves processes such as DNA synthesis and chromatin remodeling (Friedberg, 2003; Lans et al., 2012). These processes require sufficient nucleotides (Lozano & Elledge, 2000), reducing power (Rao et al., 2015), methyl and acetyl donors (Turgeon et al., 2018); and some of these are provided by mitochondria. Mitochondria are important organelles in eukaryotic cells and are responsible for energy conversion and material metabolism (Spinelli & Haigis, 2018), such as ATP, NAD+, citrate, and reactive oxygen species (ROS) (Iacobazzi & Infantino, 2014; Stein & Imai, 2012). ATP is produced by mitochondria through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (Wallace et al., 2010). The TCA cycle in the mitochondrial matrix produces NADH and FADH2, and electrons are transferred to the electron transport chain on the inner membrane (Martínez-Reyes & Chandel, 2020); in this process, NADH is oxidized to NAD+ (Wiederkehr & Demaurex, 2017). Meanwhile, mitochondrial respiratory chain complexes I and III also generate ROS including oxidative free radicals and hydrogen peroxide (Addabbo et al., 2009). These mitochondrial metabolites play an important role in nuclear DNA repair. Among these compounds, NAD+ can be used as an enzymatic reaction substrate to participate in DNA repair in such roles as a rate-limiting substance for PARP1 and SIRT1 activity (Covarrubias et al., 2021). The accumulation of ROS causes mitochondrial dysfunction and nuclear DNA damage (Srinivas et al., 2019). Dysfunctional mitochondria can downregulate ROS-mediated DNA damage through mitophagy (Bhatia-Kissova & Camougrand, 2013). Additionally, some mitochondrial functional proteins can be present in the nucleus to act as mediators of direct mitochondria-nucleus communication (Monaghan & Whitmarsh, 2015), which can translocate into the nucleus upon DNA damage. For example, mitochondrial protein HIGD1A translocates into the nucleus to participate in the regulation of HR (Chen et al., 2022). Furthermore, the mitochondrial-dependent mitophagy and apoptosis pathways can also regulate DDR responses (Fang et al., 2016). Therefore, mitochondria play an important role in the DNA damage process.
Mitochondria metabolic and nuclear DNA damage response
NAD+ is required for PARP and sirtuin activation in DDR
A main function of NAD+ is acting as a co-enzyme in cellular oxidation–reduction reactions and electron transport in the mitochondria (Yaku et al., 2018), as NAD+ is an oxidant that absorbs electrons from other molecules to reduce them to NADH. NADH can act as a reducing agent, donating the electrons it carries (Titov et al., 2016). However, increasing studies have found NAD+ also plays an important role in DNA repair in the nucleus.
PARP1 is chromatin-associated enzyme in DNA damage, which can be activated when DNA damage occurs (Liu et al., 2013). At the site of a DNA gap (i.e., a location of DNA damage), NAD+ is decomposed into nicotinamide and ADP ribose by its own glycosylation (Zhang et al., 2019); ADP ribose then forms linear or branch ADP-ribose units (also known as PARylation) catalyzed by PARP1 (Alemasova & Lavrik, 2019) (Fig. 1). It has been reported that PARP1 is immediately recruited to damaged DNA ends through its N-terminal DNA-binding motif (Ali et al., 2012), where catalytic NAD+ is used to synthesize PARylation. PARP1 can also rapidly recruit DNA damage sensors MRE11 and NBS1 to DSB sites (Haince et al., 2008). Furthermore, NAD+ is the natural substate of PARP1, and most of the existing PARP inhibitors (PARPis) mimic the nicotinamide domain of NAD+ (Rose et al., 2020), which can bind to the NAD+ binding pocket of PARP1 (Bian et al., 2019), resulting in conformational isomerism and stabilizing the reversible dissociation of DNA-PARP1, so that PARP1 continues binding to DNA (Zandarashvili et al., 2020).
Fig. 1
Mitochondria metabolic and nuclear DNA damage response. NAD+ produced by mitochondria can participate in DNA repair as a reaction substrate of PARP1 and SIRT1. Citrate produces acetyl-CoA under the catalysis of ACLY as a substrate for acetylation of proteins involved in DNA repair. Oncometabolites are structurally similar to α-KG and can block DNA repair in the nucleus. ROS can cause DNA damage and inhibit DNA repair
Sirtuins are other NAD+ -dependent proteins involved in DNA repair, cell metabolism, and mitochondrial function (Sack & Finkel, 2012). There are seven members of the sirtuin family (SIRT1-SIRT7) in mammals (Kim et al., 2014), which share a highly conserved NAD+ binding and catalytic core binding domain (Anderson et al., 2014). When sirtuins perform their deacetylation function, NAD+ is hydrolyzed, releasing the nicotinamide moiety. Sirtuins transfer the acetyl group to ADP-ribose to form a new O-acetyl-ADP-ribose product (Flick & Luscher, 2012). Sirtuins are involved in the DNA damage response by regulating cell cycle progression and DNA repair (Mei et al., 2016). Among them, SIRT1, SIRT6 and SIRT7 have been shown to be directly involved in DSB repair, which recruits repair proteins to DSB sites (Mei et al., 2016). Sirtuins regulate the activity of repair proteins by NAD+ -dependent deacetylation. For example, deacetylation of Ku70 by SIRT1 enhances Ku70 activity and NHEJ (Jeong et al., 2007) (Fig. 1). In addition, SIRT6 recruits and stabilizes DNA-PK to DSB sites through NAD+ -dependent deacetylation, thereby promoting NHEJ (McCord et al., 2009).
Mitochondrial ROS regulate DDR sensing and signaling
Mitochondrial ROS are mainly formed in electron transport chain complexes I and III. ROS are recognized as DNA damage mediators to induce multiple types of DNA damage (Mazat et al., 2020), including oxidized bases, SSB, and DSB (Maynard et al., 2009) (Fig. 1). However, most ROS-induced DNA damage is SSB (Caldecott, 2008), which can be repaired by NER or BER (Tian et al., 2015). Unrepaired SSB can also lead to stalled replication forks and replication errors (Thakur et al., 2015). Abnormal replication forks and DNA synthesis then induce replication stress in the cell, which ultimately leads to genomic instability and DSB (Zeman & Cimprich, 2014). However, ROS can also mediate DNA repair in several ways.
H2AX has been extensively studied in DNA damage. When DNA damage occurs, members of the phosphatidylinositol 3-kinase (PI-3K) family (ATM, ATR, and DNA-PK) phosphorylate H2AX on Ser139 (also called γH2AX) (Baritaud et al., 2012). γH2AX can recruit DNA repair proteins to DSB sites, including MRN complexes (MRE11/Rad50/NBS1), 53BP1, MDC1, and Rad51, to initiate DNA repair (Lee et al., 2010). When DNA damage occurs, ROS activate ATM autophosphorylation and the downstream DDR pathway (Xie et al., 2021). Wang et al. found that ROS can disrupt the binding of Ku70/Ku80 to DNA-PKcs, inhibiting DNA-PKcs and delaying the phosphorylation of H2AX and DNA repair (Wang et al., 2018). It has also been reported that continued accumulation of intracellular ROS reduces the level of H2AX; this effect is due to the interaction of H2AX with the E3 ubiquitin ligase RNF168, which polyubiquitinates and promotes its degradation by the proteasome. Furthermore, the level of γH2AX is reduced when cells are subjected to transient ROS stimulation, which leads to delayed DNA repair (Gruosso et al., 2016). Therefore, ROS can regulate DDR by regulating γH2AX levels in different ways.
Chk1 and Chk2 are downstream of ATM/ATR, which regulate and phosphorylate proteins involved in DDR (Dai & Grant, 2010). Meng et al. reported that elevated ROS levels maintain the activation of ATR-Chk1 signaling and the upregulation of DOUXA1 in cisplatin-resistant ovarian cancer cells increases ROS levels, thereby maintaining Chk1 activation, and that ROS inhibition can effectively overcome cisplatin resistance in vivo and in vitro (Meng et al., 2018). Moreover, Jiang et al. reported that curcumin-induced ROS activated Chk1/Chk2 and causes DNA damage in an MMR-dependent manner, and the free radical scavenger (N-acetyl-l-cysteine [NAC]) can effectively eliminate the phosphorylation of Chk1 and Chk2 (Jiang et al., 2010).
Other mitochondrial metabolites regulate DDR
In addition to NAD+ and ROS, mitochondria provide other metabolites involved in DNA repair, such as citrate and oncometabolites.
Citrate is an important metabolite in the TCA cycle (Iacobazzi & Infantino, 2014). Nuclear ATP-citrate lyase (ACLY) is phosphorylated in an ATM-dependent manner in response to DNA damage, and the DNA damage signaling catalyzes citrate to acetyl-CoA in the nucleus via ACLY (Fig. 1), which can be used to regulate the acetylation of histones. ACLY silencing impairs the induction of histone acetylation at DSB sites, promotes 53BP1 binding, and inhibits BRCA1 recruitment and HR (Sivanand et al., 2017).
Oncometabolites include fumarate, succinate, and 2-hydroxyglutarate (2-HG), which are TCA cycle intermediates (Fig. 1). Mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2, respectively), fumarate hydratase, and succinate dehydrogenase in human malignancies lead to the accumulation of oncometabolites in cells (Yong et al., 2020). Studies have reported that oncometabolites can interfere with the DNA repair pathway by inhibiting the activity of histone demethylase KDM4B, resulting in hypermethylation of H3K9me3 at DNA break sites. These phenomena lead to reduced recruitment of TIP60 and ATM and downstream DNA repair factors at DNA breakage sites, thereby affecting HR (Sulkowski et al., 2020). In a mouse model of AML, 2-HG induces downregulation of ATM by altering histone modifications of the ATM promoter, resulting in impaired DDR signaling (Gueble & Bindra, 2022).
Mitochondrial proteins moonlighting in the nucleus
A growing body of research has identified mitochondrial proteins with critical extra-mitochondrial moonlight. Some proteins containing mitochondrial targeting sequences (MTS) are also present in the nucleus. Nuclear translocation of mitochondrial proteins represents a new pathway whereby signals from mitochondria can directly regulate the nucleus, acting as transcription factors to regulate transcription and maintain nuclear genome integrity (Monaghan & Whitmarsh, 2015). Furthermore, some researchers also suggest that the nuclear translocation of mitochondrial proteins can regulate nuclear DNA repair.
Endonuclease G (ENDOG)
ENDOG is a mitochondrial endonuclease involved in many cellular processes, including apoptosis and paternal mitochondrial elimination (David et al., 2006; Wiehe et al., 2018). ENDOG is released from the mitochondria and translocated to the nucleus during apoptosis, where it induces GC-rich genome fragmentation and can also digest double-stranded or single-stranded DNA and DNA-RNA heteroduplexes (David et al., 2006). Under starvation, ENDOG promotes starvation-induced DNA damage through the PARP1/AMPK pathway, thereby inhibiting mTOR activity and initiating autophagy. In ENDOG-overexpressing cells, γH2AX and p-ATM are increased following etoposide treatment relative to WT cells, and KU60019, an ATM-specific inhibitor, reduce DNA damage (Wang et al., 2021) (Fig. 2). Although DNA damage induces ENDOG, which enters the nucleus from mitochondria, the mechanisms of how it enters the nucleus and regulates DNA repair need further research.
Fig. 2
Mitochondrial proteins moonlighting in the nucleus. Mitochondrial functional proteins can be localized in the nucleus and participate in DNA repair in various ways. ENDOG can promote H2AX and ATM phosphorylation involved in DNA repair. HK2 increases the expression of 53BP1 and promotes DNA repair. HIGD1A increases DNA repair by combining with RPA to enhance the binding of the 9-1-1 complex at DNA damage sites. CRIF1 binds CDK2 and regulates its nuclear translocation, promoting the phosphorylation of CDK2 at T14 and T160 in the nucleus to facilitate DNA repair. Bcl-2 inhibits HR by co-localizing with BRCA1 at the mitochondrial outer membrane to inhibit nuclear translocation of BRCA1. Bcl-2 blocks DNA repair in the nucleus by binding to the Ku70/80 complex and the combination of Bcl-2 and PARP1 can also inhibit DNA repair
HIG1 hypoxia inducible domain family member 1A (HIGD1A)
HIGD1A is a subunit of cytochrome c oxidase (COX, complex IV), which is the terminal component of the mitochondrial respiratory chain that catalyzes the reduction of oxygen to water (Hayashi et al., 2015). A recent study reported that HIGD1A translocates into the nucleus under radiation stimulation, participates in the regulation of HR in the nucleus, and mediates the radiosensitivity of tumors (Fig. 2). Irradiation can induce HIGD1A to directly interact with the nucleoporin NUP93 through a conserved sequence (amino acids 46–60) into the nucleus (Chen et al., 2022). After entering the nucleus, HIGD1A interacts with RPA to regulate the HR pathway. At the early stages of HR, HIGD1A promotes RPA loading at DSB sites and enhances chromatin binding of the 9-1-1 complex in a DNA damage-dependent manner, thereby activating the ATR-Chk1-dependent G2/M cycle damage checkpoint. For the later stages of HR, after promoting RPA-ssDNA binding, HIGD1A in turn inhibits the aberrant persistence of RPA1 foci by promoting the ubiquitination of RPA1 and inducing its eventual proteasomal degradation, enabling final completion of HR (Chen et al., 2022).
Hexokinase 2 (HK2)
HK2 is a mitochondrial metabolic enzyme that is the initial and rate-limiting enzyme in glycolysis (Shangguan et al., 2021). Thomas et al. reported that HK2 can localize to the nucleus of acute myeloid leukemia (AML) and normal hematopoietic stem and progenitor cells, and that nuclear HK2 is regulated by its phosphorylation state, which requires active import and export via IPO5 and XPO1 (Thomas et al., 2022). However, nuclear HK2 alters stem/progenitor cell function and differentiation independently of its kinase and metabolic functions, which can enhance the DNA repair (Fig. 2). Nuclear HK2 overexpression has been found to decrease the number of DSBs and the level of γH2AX and increased expression levels of nuclear 53BP1 and Rad51 after daunorubicin treatment (Thomas et al., 2022).
BCL2 apoptosis regulator (Bcl-2)
Bcl-2 is an anti-apoptotic protein that exerts anti-apoptotic function by inhibiting the release of mitochondrial cytochrome c (Kang & Reynolds, 2009). Bcl-2 has also been reported to regulate DNA damage repair (Wang et al., 2008), and its targets include PARP1, Ku70, and BRCA1 (Kang & Reynolds, 2009) (Fig. 2). Among them, targeting BRCA1 affects multiple DNA repair processes, including HR, NHEJ, BER (Laulier & Lopez, 2012; Laulier et al., 2011). Bcl-2 is localized to mitochondria, endoplasmic reticulum (ER), and outer nuclear membrane through its C-terminal α-helical transmembrane (TM) domain (Youle & Strasser, 2008). Bcl-2 co-localizes BRCA1 to mitochondria and ER through the TM domain of Bcl-2, which leads to depletion of BRCA1 in the nucleus and thus inhibits HR (Laulier et al., 2011). Ionizing radiation enhances the expression of Bcl-2 in the nucleus, which interacts with the Ku70/80 complex and inhibits its binding to DNA breakage ends (Wang et al., 2008). In addition, the direct interaction between Bcl-2 and the enzyme PARP1 can inhibit the activity of PARP1 and delay the DNA repair (Dutta et al., 2012).
CR6-interacting factor 1 (CRIF1)
CRIF1 is a mitochondrial protein required for oxidative phosphorylation complex assembly (Chang et al., 2020). A study found that CRIF1 has nuclear localization signal and is a negative regulator of cell cycle progression (Chung et al., 2003). Recent studies have found that CRIF1 can be up-regulated and translocated to the nucleus after irradiation (Fig. 2). CRIF1 interacts with the DNA damage checkpoint regulator CDK2. Upon IR treatment, CRIF1 promotes nuclear translocation of CDK2 and promotes T14/T160 phosphorylation, which ultimately facilitates G1/S checkpoint activation and DNA damage repair (Ran et al., 2019). CRIF1-CDK2 interface inhibitors F1142-3225 and F0922-0913 in combination with paclitaxel can promote the transition of cells from G0/G1 to S and G2/M phases and induce apoptosis (Sang et al., 2022).
Mitochondrial-related autophagy and apoptosis response to DDR
DDR is activated after DNA damage occurs, and cells respond to DNA damage through multiple pathways, including the initiation of DNA repair, cell cycle arrest, autophagy, and apoptosis (Badura et al., 2012). Among these, autophagy and apoptosis are closely related to determine cell survival or death. DNA damage at low levels may stimulate autophagy and antagonize apoptosis, whereas high levels of DNA damage inhibit autophagy and stimulate apoptosis (Fang et al., 2016).
Mitochondrial-related autophagy response to DDR
DDR involves the activation of a series of proteins, and some key pathways of DNA repair are closely related to the activation of mitophagy (Babbar et al., 2020). Following nonlethal doses of DNA damage, mitochondria respond in various ways, including increased mitochondrial numbers and ROS and mitophagy (Meng et al., 2021). An increasing body of research has shown that DDR can induce mitophagy, which has observed one hour after radiation. Cells attempt to retain as many mitochondria as possible to support the energy needs in the early stage of DNA damage. At later time points, mitophagy increases and cells remove excess or damaged mitochondria produced during oxidative phosphorylation (Dan et al., 2020). Studies have also shown that autophagy can scavenge ROS that cause DNA damage and plays an important role in maintaining the genome (Filomeni et al., 2015).
Following DNA damage, ATM kinases trigger multiple events to promote cell survival and facilitate repair (Biton & Ashkenazi, 2011). ATM is recruited to DSB sites to initiate DNA repair by phosphorylating H2AX (Stiff et al., 2004). Simultaneously, ATM can also induce mitophagy to promote cell survival. ATM phosphorylates and activates NF-κB essential modifier (NEMO) (Miyamoto, 2011), which enters the cytoplasm and activates Jun N-terminal kinase (JNK) (Voigt et al., 2020); JNK regulates mitophagy through phosphorylation of Bcl-2 family members (BIM) (Biton & Ashkenazi, 2011; Gross & Katz, 2017) (Fig. 3). Further, ATM in the cytoplasm is activated by ROS and can regulate mitophagy through Beclin1 in response to ROS (Guo et al., 2020). AMPK is one of the downstream targets of ATM. ATM can directly phosphorylate AMPK or activate the upstream AMPK activator liver kinase B1 (LKB1). The activated AMPK promotes mitophagy by phosphorylating ULK1 and TBK1 (Seabright et al., 2020) (Fig. 3). ATM can also activate nuclear p53, which affects cell fate as a node of the DNA damage network (Sullivan et al., 2015). In addition, the HR-related protein BRCA1 can regulate DDR-induced mitophagy. In the nucleus, BRCA1 can reduce the expression of the mitochondrial fusion proteins MFN1 and MFN2 by inhibiting their activity, thereby negatively regulating mitochondrial fusion (Chen et al., 2020). During DNA damage, BRCA1 is exported into the cytoplasm in a p53-dependent manner (Jiang et al., 2011). In the cytoplasm, BRCA1 can translocate to the mitochondrial outer membrane, enhance the activity of the AMPK signaling pathway by interacting with ATM and AMPKα kinase, and then induce the phosphorylation of mitochondrial fission factor (MFF) and mitochondrial dynamo-related protein 1 (DRP1), thereby promoting mitochondrial fission and autophagic clearance of damaged mitochondria (Chen et al., 2020) (Fig. 3). However, in the absence of BRCA1, DNA repair and mitophagy activities are impaired in breast cells, resulting in the accumulation of large numbers of damaged mitochondria and an increase in ROS (Miyahara et al., 2021).
Fig. 3
Mitochondrial-related apoptosis and autophagy response to DDR. During DNA damage, BRCA1 can export to the cytoplasm and localize to the mitochondrial outer membrane, and mediate mitochondrial translocation of ATM and AMPK to promote AMPK-induced DRP1-MFF activation and induce mitophagy. ATM can phosphorylate and activate AMPK; and activated AMPK phosphorylates ULK1 to promote mitophagy. ATM can also activate NEMO through phosphorylation, which enters the cytoplasm to activate JNK to regulate mitophagy. Phosphorylation of Ku70 modulates the affinity of Ku70 and Bax to increase apoptosis
Mitochondrial-related apoptosis response to DDR
Cells initiate apoptosis if DNA damage cannot be repaired. Endogenous apoptosis of cells is mainly achieved through mitochondria, and the release of cytochrome c from the mitochondrial intermembrane space, together with apoptotic protease-activating factor 1 (APAF1), leads to the activation of downstream caspases and the induction of death responses (Zhu et al., 2012).
If DNA cannot be repaired, ATM phosphorylates the S155 site of Ku70, which can increase the phosphorylation of the apoptosis-related transcription factor ATF2, further promoting mitochondria-dependent apoptosis (Fell et al., 2016). Phosphorylation of Ku70 can also regulate the affinity of Ku70 and Bax. Studies have found that when S6 and S51 of Ku70 are phosphorylated, the affinity of Ku70 and Bax decreases, thereby triggering the transfer of Bax to mitochondria and promoting tumor cell apoptosis (Bouley et al., 2015) (Fig. 3). It has also been reported that NBS1 directly interacts with Ku70, allowing Ku70 acetylation and Bax translocation to mitochondria, activating Bax and inducing apoptosis upon DNA damage (Iijima et al., 2008).
While DNA damage induces apoptosis, some mitochondria-dependent proteins can also inhibit DNA repair. Caspase-3 and -7 have similar substrate and inhibitor specificity, which degrade PAR and DNA fragmentation factor-45 (DFF-45) after heterologous activation. Caspase-3 and -7 also inhibit DNA repair, and initiate DNA degradation (Wolf et al., 1999). PUMA was found to bind to and inhibit the activity of cytoplasmic early mitosis 1 (EMI1) and Rad51 and promote EMI1-mediated ubiquitination and degradation of cytoplasmic Rad51, thereby inhibiting Rad51 nuclear translocation and HR (Kang et al., 2021).
Studies have found that inhibition of mitochondrial-related apoptosis can promote DNA repair. Early oocytes respond rapidly to γ-irradiation-induced DNA DSBs by activating ATM, phosphorylating the histone H2AX, and localizing Rad51 to DNA damage sites. Although the DNA repair response is initiated in a lower level, it can also lead to early oocyte apoptosis (Stringer et al., 2020). However, when apoptosis is inhibited, the oocyte can repair severe DSBs damage through HR, effectively restoring the genetic integrity of the oocyte (Stringer et al., 2020). It has also been also found that Ku80 can be cleaved by caspase-2 after brief treatment with etoposide, where D726 was identified as the major cleavage site. This cleavage promotes Ku80/DNA-PKcs interaction, thereby enhancing NHEJ-mediated DSB repair (Yan et al., 2017).
Conclusion
DNA damage affects DNA replication, transcription, and many signaling pathways, but how this damage invokes mitochondrial signaling remains uncertain. In this review, we summarize how mitochondria are involved in DDR from three perspectives. First, mitochondrial metabolites are involved in DDR, such as NAD+ participating in DNA repair by providing reaction substrates for PARP1 and sirtuins, and mitochondrial ROS affect the degradation of γH2AX and the transmission of DDR signaling in different ways. Second, some mitochondrial proteins have moonlight in the nucleus to participate in DNA repair. Third, mitochondria can participate in DDR by regulating autophagy and apoptosis to decide cell fate. In this review, we only summarized the existing research regarding the role of mitochondria in DDR; in future research, the roles of other subcellular organelles (endoplasmic reticulum, etc.) in DDR can also be investigated. At the same time, some cytoplasmic signaling pathways also regulate DNA repair, such as mTOR, PI3K; more regulators can be identified in these pathways in the future. Finally, future studies can focus on the newly discovered cell death modes such as ferroptosis and copper death in response to DDR.
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This work was supported by the National Science Fund for Excellent Young Scholars (12122510), Anhui Provincial Key R&D Program (202104a07020006).
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Xipeng Zhao and Bin Chen have contributed equally to this work.
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High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, Anhui, China
Xipeng Zhao, Bin Chen, Lijun Wu & Guoping Zhao
Institutes of Physical Science and Information Technology, Anhui University, Hefei, 230601, Anhui, China
Xipeng Zhao
Information Materials and Intelligent Sensing Laboratory of Anhui Province, Institutes of Physical Science and Information Technology, Anhui University, Hefei, 230601, Anhui, China
Lijun Wu
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Correspondence to Guoping Zhao.
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Zhao, X., Chen, B., Wu, L. et al. Role of mitochondria in nuclear DNA damage response. GENOME INSTAB. DIS. 3, 285–294 (2022). https://doi.org/10.1007/s42764-022-00088-9
Received30 July 2022
Revised06 October 2022
Accepted08 October 2022
Published20 October 2022
Issue DateDecember 2022
DOIhttps://doi.org/10.1007/s42764-022-00088-9
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