MERIT40 cooperates with BRCA2 to resolve DNA interstrand cross-links

Jiang, Qinqin; Paramasivam, Manikandan; Aressy, Bernadette; Wu, Junmin; Bellani, Marina A.; Tong, Wei; Seidman, Michael M.; Greenberg, Roger A.

doi:10.1101/gad.264192.115

Cited by 23 publications

(29 citation statements)

References 69 publications

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“…Together, the FA/BRCA proteins and associated factors form a multifunctional network that plays a critical role in managing various forms of DNA damage and replication stress (10). Although both FA and BRCA proteins are required for ICL repair, each pathway also supports nonoverlapping functions (11,12) that play different roles in how cells respond to treatment with DNA cross-linking agents.…”

mentioning

confidence: 99%

p97 Promotes a Conserved Mechanism of Helicase Unloading during DNA Cross-Link Repair

Fullbright

Rycenga

Gruber

et al. 2016

Molecular and Cellular Biology

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Interstrand cross-links (ICLs) are extremely toxic DNA lesions that create an impassable roadblock to DNA replication. When a replication fork collides with an ICL, it triggers a damage response that promotes multiple DNA processing events required to excise the cross-link from chromatin and resolve the stalled replication fork. One of the first steps in this process involves displacement of the CMG replicative helicase (comprised of Cdc45, MCM2-7, and GINS), which obstructs the underlying crosslink. Here we report that the p97/Cdc48/VCP segregase plays a critical role in ICL repair by unloading the CMG complex from chromatin. Eviction of the stalled helicase involves K48-linked polyubiquitylation of MCM7, p97-mediated extraction of CMG, and a largely degradation-independent mechanism of MCM7 deubiquitylation. Our results show that ICL repair and replication termination both utilize a similar mechanism to displace the CMG complex from chromatin. However, unlike termination, repair-mediated helicase unloading involves the tumor suppressor protein BRCA1, which acts upstream of MCM7 ubiquitylation and p97 recruitment. Together, these findings indicate that p97 plays a conserved role in dismantling the CMG helicase complex during different cellular events, but that distinct regulatory signals ultimately control when and where unloading takes place. Interstrand cross-links (ICLs) are extremely toxic DNA lesions that covalently couple both strands of the DNA duplex. Replicating cells are particularly sensitive to ICLs, which disrupt the strand separation required for DNA replication and transcription (1). Repair of ICLs is initiated primarily during S phase when a replication fork collides with the cross-link (2-4). Fork stalling triggers a damage response that involves multiple DNA processing events that promote excision of the ICL from chromatin and resolution of the stalled replication fork (5). Defects in ICL repair are associated with delays in cell cycle progression, increased chromosomal breakage, and severe sensitivity to DNA cross-linking agents. The cellular symptoms of deficient or aberrant repair are thought to underlie the molecular basis of several cancer predisposition syndromes (6), including Fanconi anemia (FA) and hereditary breast and ovarian cancer.Fanconi anemia is a rare chromosomal instability disorder caused by mutations in 1 of at least 16 different genes (7). Four of the FA genes are classified as breast/ovarian cancer susceptibility (BRCA) genes (FANCD1/BRCA2, FANCJ/BRIP1, FANCN/ PALB2, FANCO/RAD51C) (8), with recent evidence also supporting classification of BRCA1 as a new FA subtype (FANCS) (9). Together, the FA/BRCA proteins and associated factors form a multifunctional network that plays a critical role in managing various forms of DNA damage and replication stress (10). Although both FA and BRCA proteins are required for ICL repair, each pathway also supports nonoverlapping functions (11, 12) that play different roles in how cells respond to treatment with DNA cross-linking agents.Xenop...

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mentioning

confidence: 99%

p97 Promotes a Conserved Mechanism of Helicase Unloading during DNA Cross-Link Repair

Fullbright

Rycenga

Gruber

et al. 2016

Molecular and Cellular Biology

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“…Some researchers suggest that BRCA1-A complex decreases end resection activity in processes of HR repair [35,61]. On the contrary, under different experimental conditions, BRCA1-A complex increases HR repair activity [17,18,78]. One possible explanation would be that the BRCA1-A complex can be regulated by different factors in different context.…”

Section: Merit40mentioning

confidence: 89%

“…As a result, MERIT40 is essential for proper DNA damage repair, G2/M checkpoint, and cell survival [19,20]. Recently, it was suggested that MERIT40 is required for ICLs repair pathways, which is independent of BRCA2 [78]. Jiang and colleagues [78] demonstrated that end resection and HR are reduced after ICLs damage in MERIT40-null cells.…”

Section: Merit40mentioning

confidence: 99%

“…Recently, it was suggested that MERIT40 is required for ICLs repair pathways, which is independent of BRCA2 [78]. Jiang and colleagues [78] demonstrated that end resection and HR are reduced after ICLs damage in MERIT40-null cells. Another study suggested that MERIT40 might be a drug target because MERIT40 was phosphorylated by Akt, which is activated by cancer drug doxorubicin [80].…”

Section: Merit40mentioning

confidence: 99%

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Factors forming the BRCA1-A complex orchestrate BRCA1 recruitment to the sites of DNA damage

Her

Lee

Kim

et al. 2016

ABBS

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Sustaining genomic integrity is essential for preventing onset of cancers. Therefore, human cells evolve to have refined biological pathways to defend genetic materials from various genomic insults. DNA damage response and DNA repair pathways essential for genome maintenance are accomplished by cooperative executions of multiple factors including breast cancer type 1 susceptibility protein (BRCA1). BRCA1 is initially identified as an altered gene in the hereditary breast cancer patients. Since then, tremendous efforts to understand the functions of BRAC1 reveal that BRCA1 is found in distinct complexes, including BRCA1-A, BRCA1-B, BRCA1-C, and the BRCA1/ PALB2/BRCA2 complex, and plays diverse roles in a context-dependent manner. Among the complexes, BRCA1-A is critical for BRCA1 recruitment to the sites of DNA damage. Factors comprising the BRCA1-A include RAP80, CCDC98/Abraxas, BRCC36, BRCC45, BARD1, BRCA1, and MERIT40, a RAP80-associated factor. In this review, we summarize recent findings of the factors that form the BRCA1-A complex.

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“…The lethality induced by FANCD2 abrogation in BRCA2-deficient cells (Michl et al 2016) can be exploited therapeutically to treat BRCA2-deficient tumors. Similarly, the mediator of RAP80 interactions and targeting subunit of 40 kDa (MERIT40), a subunit of the receptor-associated protein 80 (RAP80) ubiquitin recognition complex involved in the targeting of BRCA1 to DNA damage sites, has recently been implicated in the processing of ICLs and could be an interesting target for anticancer therapy (Jiang et al 2015). Indeed, the increased chromosomal aberrations observed in Merit40-and Brca2-deficient mouse embryonic fibroblasts highlights the relevance of targeting MERIT40 in BRCA2-deficient tumor cells.…”

Section: Novel Therapeutic Approachesmentioning

confidence: 99%

BRCA2 functions: from DNA repair to replication fork stabilization

Fradet-Turcotte¹,

Sitz²,

Grapton³

et al. 2016

Endocrine-Related Cancer

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Maintaining genomic integrity is essential to preserve normal cellular physiology and to prevent the emergence of several human pathologies including cancer. The breast cancer susceptibility gene 2 (BRCA2, also known as the Fanconi anemia (FA) complementation group D1 (FANCD1)) is a potent tumor suppressor that has been extensively studied in DNA double-stranded break (DSB) repair by homologous recombination (HR). However, BRCA2 participates in numerous other processes central to maintaining genome stability, including DNA replication, telomere homeostasis and cell cycle progression. Consequently, inherited mutations in BRCA2 are associated with an increased risk of breast, ovarian and pancreatic cancers. Furthermore, bi-allelic mutations in BRCA2 are linked to FA, a rare chromosome instability syndrome characterized by aplastic anemia in children as well as susceptibility to leukemia and cancer. Here, we discuss the recent developments underlying the functions of BRCA2 in the maintenance of genomic integrity. The current model places BRCA2 as a central regulator of genome stability by repairing DSBs and limiting replication stress. These findings have direct implications for the development of novel anticancer therapeutic approaches.

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MERIT40 cooperates with BRCA2 to resolve DNA interstrand cross-links

Cited by 23 publications

References 69 publications

p97 Promotes a Conserved Mechanism of Helicase Unloading during DNA Cross-Link Repair

p97 Promotes a Conserved Mechanism of Helicase Unloading during DNA Cross-Link Repair

Factors forming the BRCA1-A complex orchestrate BRCA1 recruitment to the sites of DNA damage

BRCA2 functions: from DNA repair to replication fork stabilization

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