Interplay between the DNA Damage Proteins MDC1 and ATM in the Regulation of the Spindle Assembly Checkpoint

Eliezer, Yifat; Argaman, Liron; Kornowski, Maya; Roniger, Maayan; Goldberg, Michal

doi:10.1074/jbc.m113.532739

Cited by 58 publications

(64 citation statements)

References 59 publications

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“…Townsend et al reported that MDC1 directly interacts with APC/C and that MDC1-depleted cells undergo a very long mitosis (16). In contrast, Eliezer et al reported that MDC1 plays a role in the spindle assembly checkpoint (SAC) and that MDC1-depleted cells actually have a shorter mitosis (32). Our results clearly showed that MDC1 is required for normal mitotic progression and that MDC1-deficient cells display prolonged mitosis.…”

Section: Discussionsupporting

confidence: 54%

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DNA Damage Response-Independent Role for MDC1 in Maintaining Genomic Stability

Shao

Kong

et al. 2017

Molecular and Cellular Biology

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MDC1 is a central player in checkpoint activation and subsequent DNA repair following DNA damage. Although MDC1 has been studied extensively, many of its known functions, to date, pertain to the DNA damage response (DDR) pathway. Herein we report a novel function of phosphorylated MDC1 that is independent of ATM and DNA damage and is required for proper mitotic progression and maintenance of genomic stability. We demonstrate that MDC1 is an in vivo target of Plk1 and that phosphorylated MDC1 is dynamically localized to nuclear envelopes, centrosomes, kinetochores, and midbodies. Knockdown of MDC1 or abrogation of Plk1 phosphorylation of MDC1 causes a delay of the prometaphase-metaphase transition. It is significant that mice with reduced levels of MDC1 showed an elevated level of spontaneous tumors in aged animals. Our results demonstrate that MDC1 also plays a fundamentally significant role in maintenance of genomic stability through a DDR-independent pathway. KEYWORDS MDC1, genomic instability, mitosis, Plk1, phosphorylation I t has been well established that the DNA damage response (DDR) pathway is essential for the maintenance of genome stability and that dysfunction of the DDR results in tumorigenesis (1). Mediator of DNA damage checkpoint 1 (MDC1) is a large protein that contains both forkhead-associated (FHA) and BRCA1 C-terminal (BRCT) domains, both of which are frequently found in proteins involved in the DDR (2). In light of these features, several groups independently discovered the critical role of MDC1 in the DDR (3-6). Indeed, dysfunction of MDC1 has been reported to cause multiple disorders (6, 7). Genetic variants of MDC1 have been associated with Epstein-Barr virus antibody titers and radiosensitivity, both of which are associated with high risk for human cancers (8, 9). MDC1 Ϫ/Ϫ mice recapitulate many phenotypes of H2AX knockout mice, including growth retardation, male infertility, immune defects, chromosome instability, DNA repair defects, and radiation sensitivity (6, 10). Interestingly, mice heterozygous for MDC1 did not show any DNA repair defects or radiation sensitivity (6). Therefore, MDC1 is haplosufficient for the DDR pathway. However, moderately reduced expression of the MDC1 protein was found for lung cancer, breast carcinoma, gastric carcinoma, and glioma (11-13). Furthermore, single nucleotide polymorphisms (SNPs) of MDC1 that affect the MDC1 expression level have been associated with an increased risk of lung cancer (14). All of this emerging evidence is suggestive of other MDC1 functions that are unrelated to DDR signaling. In support of this, MDC1 was shown to interact with anaphase-promoting complex/cyclosome (APC/C), thus regulating mitotic progression (15,16). Therefore, it is crucial to discern new MDC1 functions in order to fully understand how MDC1 suppresses tumorigenesis and how reduced expression of MDC1 predisposes cells to tumorigenicity.

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Section: Discussionsupporting

confidence: 54%

“…In addition to the DNA damage signaling pathway, it was recently proposed that MDC1 is involved in the regulation of mitosis (16,32). However, the exact role of MDC1 and its regulation during normal cell cycle progression remain elusive.…”

Section: Discussionmentioning

confidence: 99%

DNA Damage Response-Independent Role for MDC1 in Maintaining Genomic Stability

Shao

Kong

et al. 2017

Molecular and Cellular Biology

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“…This may not be too surprising given the reported lack of ATM activation in GV stage oocytes following DNA damage (Marangos & Carroll 2012). This contrasts with somatic cells where ATM has been implicated in SAC activation after nocodazole treatment (Eliezer et al 2014). Another DDR protein, MDC1, has also been suggested to be able to directly interact with the APC, an interaction that is heightened after DNA damage (Coster et al 2007).…”

Section: R20 J K Collins and K T Jonescontrasting

confidence: 42%

DNA damage responses in mammalian oocytes

Collins¹,

Jones²

2016

Reproduction

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DNA damage acquired during meiosis can lead to infertility and miscarriage. Hence, it should be important for an oocyte to be able to detect and respond to such events in order to make a healthy egg. Here, the strategies taken by oocytes during their stages of growth to respond to DNA damaging events are reviewed. In particular, recent evidence of a novel pathway in fully grown oocytes helps prevent the formation of mature eggs with DNA damage. It has been found that fully grown germinal vesicle stage oocytes that have been DNA damaged do not arrest at this point in meiosis, but instead undergo meiotic resumption and stall during the first meiotic division. The Spindle Assembly Checkpoint, which is a well-known mitotic pathway employed by somatic cells to monitor chromosome attachment to spindle microtubules, appears to be utilised by oocytes also to respond to DNA damage. As such maturing oocytes are arrested at metaphase I due to an active Spindle Assembly Checkpoint. This is surprising given this checkpoint has been previously studied in oocytes and considered to be weak and ineffectual because of its poor ability to be activated in response to microtubule attachment errors. Therefore, the involvement of the Spindle Assembly Checkpoint in DNA damage responses of mature oocytes during meiosis I uncovers a novel second function for this ubiquitous cellular checkpoint. Reproduction (2016) 152 R15-R22cryopreservation of embryos and oocytes (Maltaris et al. 2007, ASRM 2013, Roness et al. 2014, Skaznik-Wikiel et al. 2015. Unfortunately, these methods cannot be applied to all. One limitation of this technique is that a partner, or willingness to use a donor, is required to provide sperm. Hormonal suppression of ovaries during cancer treatment is another option for women; however, the use of such drugs has potential associated risks such as interference with the cancer treatment or survival of eggs with DNA damage (Roness et al. 2014).However, the major limitation of cryopreservation methods is that they can only be used in post-pubertal women. Therefore, there are currently no established options for young pre-pubertal girls (Skaznik-Wikiel et al. 2015). Experimental options include ovarian tissue cryopreservation, but this has a variety of risks associated with it (Maltaris et al. 2007, Skaznik-Wikiel et al. 2015.In this review, we will focus on the various strategies that oocytes elicit, in the adult, upon damage to their DNA. This includes the apoptosis of primordial follicles, evasion of the G2/M checkpoint and a metaphase arrest induced by DNA damage. Programmed doublestrand breaks (DSBs) occur in foetal life during meiotic recombination and pose a potential threat to oocytes if left unrepaired. However, only responses to exogenous sources of DNA damage will be discussed here. R16 J K Collins and K T JonesReproduction (2016) 152 R15-R22www.reproduction-online.org Primordial follicle apoptosis after DNA damageAt birth, the reserve of oocytes has been established and is held within primordial follicles ar...

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“…Thus, there is a critical need to develop more effective treatments for NPC. NFBD1 (nuclear factor with BRCT domain protein 1), also known as MDC1 (mediator of DNA damage checkpoint protein 1), is a recently identified nuclear protein that regulates many aspects of the DNA damage response (DDR) pathway, such as the intra-S phase checkpoint, the G2/M checkpoint, the spindle-assembly checkpoint and the formation of NBS/MRE/Rad50 (MRN complex), 53BP1 and BRCA1 foci [7][8][9][10][11]. Human NFBD1 comprises 2089 amino acid residues and has a predicted molecular weight of *220 kDa.…”

Section: Introductionmentioning

confidence: 99%

Knockdown of NFBD1/MDC1 enhances chemosensitivity to cisplatin or 5-fluorouracil in nasopharyngeal carcinoma CNE1 cells

et al. 2016

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Nasopharyngeal carcinoma (NPC) is a rare but highly invasive cancer that is prevalent among people of southern Chinese ancestry in southern China and Southeast Asia. Radiotherapy and cisplatin (CDDP)-based chemotherapy are the main treatment options. Unfortunately, disease response to concurrent chemoradiotherapy varies among patients with NPC, and many cases are resistant to CDDP and radiotherapy. NFBD1 functions in cell cycle checkpoint activation and DNA repair following DNA damage. In this study, we identified the NFBD1 as a tractable molecular target to chemosensitize NPC cells. NFBD1 expression in NPC CNE1 cell lines was depleted using lentivirus-mediated short hairpin RNA, and the elevated sensitivity of these NFBD1-inhibited NPC cells to therapeutic reagent CDDP and 5-fluorouracil (5-FU) was evaluated using MTS assays. Flow cytometry analysis also showed that NFBD1 knockdown led to an obvious induction of apoptosis in CDDP- or 5-FU-treated CNE1 cells. Furthermore, we implicated the involvement of NFBD1 in Rad51 and DNA-PKcs foci formation following CDDP or 5-FU chemotherapy. In conclusion, NFBD1 knockdown improves the chemosensitivity of NPC cells by inhibiting cell growth and promoting apoptosis through the impairment of DNA damage repair, suggesting NFBD1 as a novel therapeutic target for NPC.

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Interplay between the DNA Damage Proteins MDC1 and ATM in the Regulation of the Spindle Assembly Checkpoint

Cited by 58 publications

References 59 publications

DNA Damage Response-Independent Role for MDC1 in Maintaining Genomic Stability

DNA Damage Response-Independent Role for MDC1 in Maintaining Genomic Stability

DNA damage responses in mammalian oocytes

Knockdown of NFBD1/MDC1 enhances chemosensitivity to cisplatin or 5-fluorouracil in nasopharyngeal carcinoma CNE1 cells

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