hMSH5 Facilitates the Repair of Camptothecin-induced Double-strand Breaks through an Interaction with FANCJ

Xu, Yongfen; Wu, Xiaopan; Her, Chengtao

doi:10.1074/jbc.m115.642884

Cited by 17 publications

(11 citation statements)

References 59 publications

(75 reference statements)

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“…Confounding this suggestion, however, is the observation that loss of BLM helicase in mouse meiosis is associated with increased COs (Holloway et al 2010), while others have suggested that BLM and FANCJ may act coordinately in mitotic cells to unwind DNA at the end of a DSB and thereby to suppress repair by HR (Xu et al 2015). The upregulated BLM localization through prophase I is similar to that seen in mutants lacking the class II crossover regulator, MUS81 (Holloway et al 2008), suggesting that BLM participates in recruiting additional MLH1-MLH3-mediated crossover events in the absence of either MUS81 or FANCJ.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have demonstrated that FANCJ interacts with the MutS homolog, MSH5 (Xu et al 2015). MSH5 is a component of the MutSγ complex alongside MSH4, which functions as an essential regulator of the predominant crossover pathway during prophase I (Hollingsworth et al 1995; Kneitz et al 2000; Paquis-Flucklinger et al 1997; Ross-Macdonald and Roeder 1994; Snowden et al 2008).…”

Section: Discussionmentioning

confidence: 99%

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FancJ (Brip1) loss-of-function allele results in spermatogonial cell depletion during embryogenesis and altered processing of crossover sites during meiotic prophase I in mice

et al. 2015

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Fancj, the gene associated with Fanconi anemia (FA) Complementation Group J, encodes a DNA helicase involved in homologous recombination repair and the cellular response to replication stress. FANCJ functions in part through its interaction with key DNA repair proteins, including MutL homolog-1 (MLH1), Breast Cancer Associated gene-1 (BRCA1), and Bloom syndrome helicase (BLM). All three of these proteins are involved in a variety of events that ensure genome stability, including the events of DNA double strand break (DSB) repair during prophase I of meiosis. Meiotic DSBs are repaired through homologous recombination resulting in non-crossovers (NCO) or crossovers (CO). The frequency and placement of COs are stringently regulated to ensure that each chromosome receives at least one CO event, and that longer chromosomes receive at least one additional CO, thus facilitating the accurate segregation of homologous chromosomes at the first meiotic division. In the present study, we investigated the role of Fancj during prophase I using a gene trap mutant allele. FancjGT/GT mutants are fertile, but their testes are very much smaller than wild-type litter-mates, predominantly as a result of impeded spermatogonial proliferation and mildly increased apoptosis during testis development in the fetus. This defect in spermatogonial proliferation is consistent with mutations in other FA genes. During prophase I, early events of synapsis and DSB induction/repair appear mostly normal in FancjGT/GT males, and the FANCJ-interacting protein BRCA1 assembles normally on meiotic chromosome cores. However, MLH1 focus frequency is increased in FancjGT/GT males, indicative of increased DSB repair via CO, and is concomitant with increased chiasmata at diakinesis. This increase in COs in the absence of FANCJ is associated with increased localization of BLM helicase protein, indicating that BLM may facilitate the increased rate of crossing over in FancjGT/GT males. Taken together, these results demonstrate a critical role for FANCJ in spermatogenesis at two stages: firstly in the proliferative activity that gives rise to the full complement of testicular spermatogonia and secondly in the establishment of appropriate CO numbers during prophase I.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

FancJ (Brip1) loss-of-function allele results in spermatogonial cell depletion during embryogenesis and altered processing of crossover sites during meiotic prophase I in mice

et al. 2015

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“…Consistent with this, the hMSH5 C85T polymorphism poses an increased risk of sperm DNA damage and male infertility in Chinese populations (Xu et al, 2010;Ji et al, 2012). Given the fact that hMSH5 is expressed in primary and cancer cells and the expression of hMSH5 can be induced by radiation treatment (Tompkins et al, 2009;Xu et al, 2015), it is conceivable that radiation-induced DNA lesions in germ cells may not be properly repaired on the hMSH5 P29S background, thereby leading to a long-lasting effect on spermatogenesis. The current observations warrant future exploration of the potential effect of hMSH5 on DNA damage repair in spermatogonial stem cells.…”

Section: Discussionmentioning

confidence: 74%

The polymorphichMSH5C85T allele augments radiotherapy-induced spermatogenic impairment

et al. 2016

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SUMMARYThe hMSH5 C85T polymorphism (encoding hMSH5 P29S) is associated with male infertility and radiation-induced apoptotic response. To date, however, the potential association of hMSH5 C85T polymorphism with DNA damage accumulation in spermatozoa of cancer patients treated with radiotherapy is largely unknown. We investigated hMSH5 C85T allele and genotype frequencies, routine semen analysis and sperm DNA Fragmentation Index (DFI) in 113 testicular germ cell tumor (TGCT) patients before and after radiotherapy. The hMSH5 C85T allele is not associated with the occurrence of TGCT. However, in comparison with the CC genotype, TGCT patients with the CT + TT genotypes showed significantly altered sperm counts, sperm morphology and DFI after radiotherapy. Finally, the results of the DSB repair assay demonstrated that hMSH5 P29S could enhance radiotherapy-induced DNA damage by unleashing error-prone non-homologous end joining. Together, our studies indicate that the hMSH5 C85T variation could have an impact on the severity of radiotherapy-provoked long-term side effects through compromising the repair of radiationinduced DNA lesions.

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“…With no surprise, many genes involved in SSB and DSB repair are on the list, such as PARP1, XRCC1, PNKP, TDP1 for SSB repair; MRN, ATM-CHK2, ATR-CHK1 for DSB signaling; BRCA1/2, XRCC2, XRCC3 for HR. Most recently, the hMSH5-FANCJ complex has also been implicated to play a role in CPT-induced DNA damage response and repair [ 64 ]. Mutations in the binding partners of these repair factors are also likely to sensitize cells to CPT treatment.…”

Section: Pathways Involved In the Repair Of Cpt-induced Dna Lesionmentioning

confidence: 99%

Inhibition of Topoisomerase (DNA) I (TOP1): DNA Damage Repair and Anticancer Therapy

Her

2015

Biomolecules

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113

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Most chemotherapy regimens contain at least one DNA-damaging agent that preferentially affects the growth of cancer cells. This strategy takes advantage of the differences in cell proliferation between normal and cancer cells. Chemotherapeutic drugs are usually designed to target rapid-dividing cells because sustained proliferation is a common feature of cancer [1,2]. Rapid DNA replication is essential for highly proliferative cells, thus blocking of DNA replication will create numerous mutations and/or chromosome rearrangements—ultimately triggering cell death [3]. Along these lines, DNA topoisomerase inhibitors are of great interest because they help to maintain strand breaks generated by topoisomerases during replication. In this article, we discuss the characteristics of topoisomerase (DNA) I (TOP1) and its inhibitors, as well as the underlying DNA repair pathways and the use of TOP1 inhibitors in cancer therapy.

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hMSH5 Facilitates the Repair of Camptothecin-induced Double-strand Breaks through an Interaction with FANCJ

Cited by 17 publications

References 59 publications

FancJ (Brip1) loss-of-function allele results in spermatogonial cell depletion during embryogenesis and altered processing of crossover sites during meiotic prophase I in mice

FancJ (Brip1) loss-of-function allele results in spermatogonial cell depletion during embryogenesis and altered processing of crossover sites during meiotic prophase I in mice

The polymorphichMSH5C85T allele augments radiotherapy-induced spermatogenic impairment

Inhibition of Topoisomerase (DNA) I (TOP1): DNA Damage Repair and Anticancer Therapy

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