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Nicholas E Mamrak, Akiko Shimamura, Niall G Howlett
Fanconi anemia (FA) is a rare autosomal and X-linked genetic disease characterized by congenital abnormalities, progressive bone marrow failure (BMF), and increased cancer risk during early adulthood. The median lifespan for FA patients is approximately 33years. The proteins encoded by the FA genes function together in the FA-BRCA pathway to repair DNA damage and to maintain genome stability. Within the past two years, five new FA genes have been identified-RAD51/FANCR, BRCA1/FANCS, UBE2T/FANCT, XRCC2/FANCU, and REV7/FANCV-bringing the total number of disease-causing genes to 21...
October 13, 2016: Blood Reviews
Liu Feng, Wang Wei, Zhang Heng, Han Yantao, Wang Chunbo
REV7 (also known as MAD2L2) is a multifunctional protein involved in DNA damage tolerance, cell cycle regulation, gene expression, and carcinogenesis. Although its expression is reportedly associated with poor prognosis in several kinds of human cancers, the significance of REV7 expression in breast malignancies is unclear. In this study, REV7 was found to be increased in breast cancer. We found that knockdown of REV7 inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of breast cancer cells...
2016: Oncology Research
Dominique Bluteau, Julien Masliah-Planchon, Connor Clairmont, Alix Rousseau, Raphael Ceccaldi, Catherine Dubois d'Enghien, Olivier Bluteau, Wendy Cuccuini, Stéphanie Gachet, Régis Peffault de Latour, Thierry Leblanc, Gérard Socié, André Baruchel, Dominique Stoppa-Lyonnet, Alan D D'Andrea, Jean Soulier
Fanconi anemia (FA) is a recessive genetic disease characterized by congenital abnormalities, chromosome instability, progressive bone marrow failure (BMF), and a strong predisposition to cancer. Twenty FA genes have been identified, and the FANC proteins they encode cooperate in a common pathway that regulates DNA crosslink repair and replication fork stability. We identified a child with severe BMF who harbored biallelic inactivating mutations of the translesion DNA synthesis (TLS) gene REV7 (also known as MAD2L2), which encodes the mutant REV7 protein REV7-V85E...
September 1, 2016: Journal of Clinical Investigation
Marcelo L Actis, Nigus D Ambaye, Benjamin J Evison, Youming Shao, Murugendra Vanarotti, Akira Inoue, Ezelle T McDonald, Sotaro Kikuchi, Richard Heath, Kodai Hara, Hiroshi Hashimoto, Naoaki Fujii
DNA interstrand crosslink (ICL) repair (ICLR) has been implicated in the resistance of cancer cells to ICL-inducing chemotherapeutic agents. Despite the clinical significance of ICL-inducing chemotherapy, few studies have focused on developing small-molecule inhibitors for ICLR. The mammalian DNA polymerase ζ, which comprises the catalytic subunit REV3L and the non-catalytic subunit REV7, is essential for ICLR. To identify small-molecule compounds that are mechanistically capable of inhibiting ICLR by targeting REV7, high-throughput screening and structure-activity relationship (SAR) analysis were performed...
September 15, 2016: Bioorganic & Medicinal Chemistry
Daniela Kurfurstova, Jirina Bartkova, Radek Vrtel, Alena Mickova, Alena Burdova, Dusana Majera, Martin Mistrik, Milan Kral, Frederic R Santer, Jan Bouchal, Jiri Bartek
The DNA damage checkpoints provide an anti-cancer barrier in diverse tumour types, however this concept has remained unexplored in prostate cancer (CaP). Furthermore, targeting DNA repair defects by PARP1 inhibitors (PARPi) as a cancer treatment strategy is emerging yet requires suitable predictive biomarkers. To address these issues, we performed immunohistochemical analysis of multiple markers of DNA damage signalling, oxidative stress, DNA repair and cell cycle control pathways during progression of human prostate disease from benign hyperplasia, through intraepithelial neoplasia to CaP, complemented by genetic analyses of TMPRSS2-ERG rearrangement and NQO1, an anti-oxidant factor and p53 protector...
June 2016: Molecular Oncology
Yulia Pustovalova, Mariana T Q Magalhães, Sanjay D'Souza, Alessandro A Rizzo, George Korza, Graham C Walker, Dmitry M Korzhnev
Translesion synthesis (TLS) is a mutagenic branch of cellular DNA damage tolerance that enables bypass replication over DNA lesions carried out by specialized low-fidelity DNA polymerases. The replicative bypass of most types of DNA damage is performed in a two-step process of Rev1/Polζ-dependent TLS. In the first step, a Y-family TLS enzyme, typically Polη, Polι, or Polκ, inserts a nucleotide across a DNA lesion. In the second step, a four-subunit B-family DNA polymerase Polζ (Rev3/Rev7/PolD2/PolD3 complex) extends the distorted DNA primer-template...
April 5, 2016: Biochemistry
Jutta Zimmer, Eliana M C Tacconi, Cecilia Folio, Sophie Badie, Manuela Porru, Kerstin Klare, Manuela Tumiati, Enni Markkanen, Swagata Halder, Anderson Ryan, Stephen P Jackson, Kristijan Ramadan, Sergey G Kuznetsov, Annamaria Biroccio, Julian E Sale, Madalena Tarsounas
G-quadruplex (G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers. Stalled replication forks can be stabilized and restarted by homologous recombination (HR), which also repairs DNA double-strand breaks (DSBs) arising at collapsed forks. We have previously shown that HR facilitates telomere replication. Here, we demonstrate that the replication efficiency of guanine-rich (G-rich) telomeric repeats is decreased significantly in cells lacking HR. Treatment with the G4-stabilizing compound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4 formation drives telomere instability...
February 4, 2016: Molecular Cell
Audesh Bhat, Zhaojia Wu, Veronica M Maher, J Justin McCormick, Wei Xiao
The spindle assembly checkpoint (SAC) acts as a guardian against cellular threats that may lead to chromosomal missegregation and aneuploidy. Mad2, an anaphase-promoting complex/cyclosome-Cdc20 (APC/C(Cdc20)) inhibitor, has an additional homolog in mammals known as Mad2B, Mad2L2 or Rev7. Apart from its role in Polζ-mediated translesion DNA synthesis and double-strand break repair, Rev7 is also believed to inhibit APC/C by negatively regulating Cdh1. Here we report yet another function of Rev7 in cultured human cells...
2015: Cell Cycle
Sosei Okina, Nobuyuki Yanagisawa, Maki Yokoyama, Yasutaka Sakurai, Yoshiko Numata, Atsuko Umezawa, Masaaki Higashihara, Yoshiki Murakumo
REV7 is a multifunctional protein involved in DNA damage tolerance, cell-cycle regulation, gene expression, and carcinogenesis. Although its expression is reportedly associated with poor prognosis in human solid tissue cancers, the significance of REV7 expression in hematopoietic malignancies is unclear. This study evaluated the prognostic significance of REV7 expression in patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab-combined chemotherapy. Using immunohistochemistry, we analyzed 83 specimens of de novo DLBCL [38 germinal center B-cell-like (GCB) and 45 non-GCB DLBCLs] treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone for REV7 expression...
December 2015: International Journal of Hematology
Shiqian Qi, Do Jin Kim, Goran Stjepanovic, James H Hurley
The ULK1 complex, consisting of the ULK1 protein kinase itself, FIP200, Atg13, and Atg101, controls the initiation of autophagy in animals. We determined the structure of the complex of the human Atg13 HORMA (Hop1, Rev7, Mad2) domain in complex with the full-length HORMA domain-only protein Atg101. The two HORMA domains assemble with an architecture conserved in the Mad2 conformational heterodimer and the S. pombe Atg13-Atg101 HORMA complex. The WF finger motif that is essential for function in human Atg101 is sequestered in a hydrophobic pocket, suggesting that the exposure of this motif is regulated...
October 6, 2015: Structure
J Ye, T Chu, R Li, Y Niu, B Jin, J Xia, M Shao, B Han
Lung cancer is the greatest contributor to tumor-derived death. Traditionally, platinum-based chemotherapies are the primary treatment for most patients. However, intrinsic drug resistance and side effects limit the efficacy of platinum-based chemotherapies. Previous studies demonstrated that Pol ζ can modulate cellular sensitivity to chemotherapy. The primary aim of this study was to investigate the potential role of the polymorphism of Pol ζ in platinum-based chemotherapy tolerance and side effects. A total of 663 patients who were newly histologically diagnosed with advanced NSCLC were enrolled...
2015: Neoplasma
Masashi Uchiyama, Junko Terunuma, Fumio Hanaoka
Translesion DNA synthesis provides an alternative DNA replication mechanism when template DNA is damaged. In fission yeast, Eso1 (polη), Kpa1/DinB (polκ), Rev1, and Polζ (a complex of Rev3 and Rev7) have been identified as translesion synthesis polymerases. The enzymatic characteristics and protein-protein interactions of these polymerases have been intensively characterized; however, how these proteins are regulated during the cell cycle remains unclear. Therefore, we examined the cell cycle oscillation of translesion polymerases...
2015: PloS One
Jung Hee Lee, Yong Hun Jo, Bharat Bhusan Patnaik, Ki Beom Park, Hamisi Tindwa, Gi Won Seo, Raman Chandrasekar, Yong Seok Lee, Yeon Soo Han
Autophagy is a process that is necessary during starvation, as it replenishes metabolic precursors by eliminating damaged organelles. Autophagy is mediated by more than 35 autophagy-related (Atg) proteins that participate in the nucleation, elongation, and curving of the autophagosome membrane. In a pursuit to address the role of autophagy during development and immune resistance of the mealworm beetle, Tenebrio molitor, we screened ATG gene sequences from the whole-larva transcriptome database. We identified a homolog of ATG13 gene in T...
2015: Frontiers in Physiology
Hironori Suzuki, Takeshi Kaizuka, Noboru Mizushima, Nobuo N Noda
Atg101 is an essential component of the autophagy-initiating ULK complex in higher eukaryotes, but it is absent from the functionally equivalent Atg1 complex in budding yeast. Here, we report the crystal structure of the fission yeast Atg101-Atg13 complex. Atg101 has a Hop1, Rev7 and Mad2 (HORMA) architecture similar to that of Atg13. Mad2 HORMA has two distinct conformations (O-Mad2 and C-Mad2), and, intriguingly, Atg101 resembles O-Mad2 rather than the C-Mad2-like Atg13. Atg13 HORMA from higher eukaryotes possesses an inherently unstable fold, which is stabilized by Atg101 via interactions analogous to those between O-Mad2 and C-Mad2...
July 2015: Nature Structural & Molecular Biology
Abdolrahim Abbasi, Maryam Khalaj, Kouyou Akiyama, Yoshiyuki Mukai, Hirokazu Matsumoto, Tomas J Acosta, Neveen Said, Midori Yoshida, Tetsuo Kunieda
Rev7 is a subunit of Polζ, one of the translesion DNA synthesis (TLS) polymerases involved in DNA damage repair. We recently found that Rev7 is also essential for germ cell development in mouse. In the present study, we found the development of ovarian tumors in Rev7 mutant mouse, suggesting the involvement of TLS deficiency in the etiology of ovarian tumor. The Rev7 mutant mice showed complete lack of oocytes and follicles in the ovary. The lack of follicles causes a significant increase of gonadotropin level and an increase in the proliferation of ovarian cells...
September 5, 2015: Molecular and Cellular Endocrinology
Mehdi Pirouz, Ali Rahjouei, Farnaz Shamsi, Kolja Neil Eckermann, Gabriela Salinas-Riester, Claudia Pommerenke, Michael Kessel
The induction and maintenance of pluripotency requires the expression of several core factors at appropriate levels (Oct4, Sox2, Klf4, Prdm14). A subset of these proteins (Oct4, Sox2, Prdm14) also plays crucial roles for the establishment of primordial germ cells (PGCs). Here we demonstrate that the Mad2l2 (MAD2B, Rev7) gene product is not only required by PGCs, but also by pluripotent embryonic stem cells (ESCs), depending on the growth conditions. Mad2l2(-/-) ESCs were unstable in LIF/serum medium, and differentiated into primitive endoderm...
2015: Cell Cycle
Julian E Sale
No abstract text is available yet for this article.
June 12, 2015: EMBO Journal
Gerben Vader
During meiotic and mitotic cell divisions, numerous chromosomal processes are essential for the faithful transmission of the genetic material. Pch2(TRIP13), a generally conserved member of the AAA(+) ATPase (AAA(+)--ATPases associated with diverse cellular activities) family of ATPases, is rapidly emerging as a key regulator of specific chromosomal events. During the meiotic program, it is involved in controlling G2/prophase processes such as DNA break formation and recombination, checkpoint signaling, and chromosome synapsis...
September 2015: Chromosoma
Guotai Xu, J Ross Chapman, Inger Brandsma, Jingsong Yuan, Martin Mistrik, Peter Bouwman, Jirina Bartkova, Ewa Gogola, Daniël Warmerdam, Marco Barazas, Janneke E Jaspers, Kenji Watanabe, Mark Pieterse, Ariena Kersbergen, Wendy Sol, Patrick H N Celie, Philip C Schouten, Bram van den Broek, Ahmed Salman, Marja Nieuwland, Iris de Rink, Jorma de Ronde, Kees Jalink, Simon J Boulton, Junjie Chen, Dik C van Gent, Jiri Bartek, Jos Jonkers, Piet Borst, Sven Rottenberg
Error-free repair of DNA double-strand breaks (DSBs) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway. In the absence of BRCA1-mediated HR, the administration of PARP inhibitors induces synthetic lethality of tumour cells of patients with breast or ovarian cancers. Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration. Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases...
May 28, 2015: Nature
Vera Boersma, Nathalie Moatti, Sandra Segura-Bayona, Marieke H Peuscher, Jaco van der Torre, Brigitte A Wevers, Alexandre Orthwein, Daniel Durocher, Jacqueline J L Jacobs
Appropriate repair of DNA lesions and the inhibition of DNA repair activities at telomeres are crucial to prevent genomic instability. By fuelling the generation of genetic alterations and by compromising cell viability, genomic instability is a driving force in cancer and ageing. Here we identify MAD2L2 (also known as MAD2B or REV7) through functional genetic screening as a novel factor controlling DNA repair activities at mammalian telomeres. We show that MAD2L2 accumulates at uncapped telomeres and promotes non-homologous end-joining (NHEJ)-mediated fusion of deprotected chromosome ends and genomic instability...
May 28, 2015: Nature
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