scholarly journals Fanconi Anemia FANCG Protein in Mitigating Radiation- and Enzyme-Induced DNA Double-Strand Breaks by Homologous Recombination in Vertebrate Cells

2003 ◽  
Vol 23 (15) ◽  
pp. 5421-5430 ◽  
Author(s):  
Kazuhiko Yamamoto ◽  
Masamichi Ishiai ◽  
Nobuko Matsushita ◽  
Hiroshi Arakawa ◽  
Jane E. Lamerdin ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Fanconi Anemia ◽  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Chromosome Breakage ◽  
Breast Cancer Susceptibility ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Brca1 And Brca2 ◽  
Strand Breaks

ABSTRACT The rare hereditary disorder Fanconi anemia (FA) is characterized by progressive bone marrow failure, congenital skeletal abnormality, elevated susceptibility to cancer, and cellular hypersensitivity to DNA cross-linking chemicals and sometimes other DNA-damaging agents. Molecular cloning identified six causative genes (FANCA, -C, -D2, -E, -F, and -G) encoding a multiprotein complex whose precise biochemical function remains elusive. Recent studies implicate this complex in DNA damage responses that are linked to the breast cancer susceptibility proteins BRCA1 and BRCA2. Mutations in BRCA2, which participates in homologous recombination (HR), are the underlying cause in some FA patients. To elucidate the roles of FA genes in HR, we disrupted the FANCG/XRCC9 locus in the chicken B-cell line DT40. FANCG-deficient DT40 cells resemble mammalian fancg mutants in that they are sensitive to killing by cisplatin and mitomycin C (MMC) and exhibit increased MMC and radiation-induced chromosome breakage. We find that the repair of I-SceI-induced chromosomal double-strand breaks (DSBs) by HR is decreased ∼9-fold in fancg cells compared with the parental and FANCG-complemented cells. In addition, the efficiency of gene targeting is mildly decreased in FANCG-deficient cells, but depends on the specific locus. We conclude that FANCG is required for efficient HR-mediated repair of at least some types of DSBs.

scholarly journals The BRCA2-MEILB2-BRME1 complex governs meiotic recombination and impairs the mitotic BRCA2-RAD51 function in cancer cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jingjing Zhang ◽  
Manickam Gurusaran ◽  
Yasuhiro Fujiwara ◽  
Kexin Zhang ◽  
Meriem Echbarthi ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Breast Cancer Susceptibility ◽  
Double Strand Breaks ◽  
Breast Cancer Susceptibility Gene ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
C Terminus ◽  
Self Association ◽  
Cancer Susceptibility Gene

AbstractBreast cancer susceptibility gene II (BRCA2) is central in homologous recombination (HR). In meiosis, BRCA2 binds to MEILB2 to localize to DNA double-strand breaks (DSBs). Here, we identify BRCA2 and MEILB2-associating protein 1 (BRME1), which functions as a stabilizer of MEILB2 by binding to an α-helical N-terminus of MEILB2 and preventing MEILB2 self-association. BRCA2 binds to the C-terminus of MEILB2, resulting in the formation of the BRCA2-MEILB2-BRME1 ternary complex. In Brme1 knockout (Brme1−/−) mice, the BRCA2-MEILB2 complex is destabilized, leading to defects in DSB repair, homolog synapsis, and crossover formation. Persistent DSBs in Brme1−/− reactivate the somatic-like DNA-damage response, which repairs DSBs but cannot complement the crossover formation defects. Further, MEILB2-BRME1 is activated in many human cancers, and somatically expressed MEILB2-BRME1 impairs mitotic HR. Thus, the meiotic BRCA2 complex is central in meiotic HR, and its misregulation is implicated in cancer development.

Functions of BRCA1 and BRCA2 in the biological response to DNA damage

2001 ◽  
Vol 114 (20) ◽  
pp. 3591-3598 ◽  
Author(s):  
Ashok R. Venkitaraman
Keyword(s):  
Dna Damage ◽  
Mammalian Cells ◽  
Cancer Susceptibility ◽  
Biological Response ◽  
Breast Cancer Susceptibility ◽  
Dna Double Strand Breaks ◽  
Brca1 And Brca2 ◽  
Strand Breaks ◽  
Cancer Susceptibility Genes ◽  
And Function

Inheritance of one defective copy of either of the two breast-cancer-susceptibility genes, BRCA1 and BRCA2, predisposes individuals to breast, ovarian and other cancers. Both genes encode very large protein products; these bear little resemblance to one another or to other known proteins, and their precise biological functions remain uncertain. Recent studies reveal that the BRCA proteins are required for maintenance of chromosomal stability in mammalian cells and function in the biological response to DNA damage. The new work suggests that, although the phenotypic consequences of their disruption are similar, BRCA1 and BRCA2 play distinct roles in the mechanisms that lead to the repair of DNA double-strand breaks.

Exploring the roles of PALB2 at the crossroads of DNA repair and cancer

2014 ◽  
Vol 460 (3) ◽  
pp. 331-342 ◽  
Author(s):  
Joris Pauty ◽  
Amélie Rodrigue ◽  
Anthony Couturier ◽  
Rémi Buisson ◽  
Jean-Yves Masson
Keyword(s):  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Developmental Abnormalities ◽  
Strand Breaks ◽  
Primary Focus ◽  
Biallelic Mutations ◽  
A Current

PALB2 [partner and localizer of BRCA2 (breast cancer early-onset 1)] has emerged as a key player in the maintenance of genome integrity. Biallelic mutations in PALB2 cause FA (Fanconi's anaemia) subtype FA-N, a devastating inherited disorder marked by developmental abnormalities, bone marrow failure and childhood cancer susceptibility, whereas monoallelic mutations predispose to breast, ovarian and pancreatic cancer. The tumour suppressor role of PALB2 has been intimately linked to its ability to promote HR (homologous recombination)-mediated repair of DNA double-strand breaks. Because PALB2 lies at the crossroads between FA, HR and cancer susceptibility, understanding its function has become the primary focus of several studies. The present review discusses a current synthesis of the contribution of PALB2 to these pathways. We also provide a molecular description of FA- or cancer-associated PALB2 mutations.

Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1329-1336 ◽  
Author(s):  
Jean Soulier ◽  
Thierry Leblanc ◽  
Jérôme Larghero ◽  
Hélène Dastot ◽  
Akiko Shimamura ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Somatic Mosaicism ◽  
Chromosome Breakage ◽  
Peripheral Blood Lymphocytes ◽  
Specific Analysis ◽  
Number Of Patients ◽  
Chromosome Fragility

AbstractFanconi anemia (FA) is characterized by congenital abnormalities, bone marrow failure, chromosome fragility, and cancer susceptibility. Eight FA-associated genes have been identified so far, the products of which function in the FA/BRCA pathway. A key event in the pathway is the monoubiquitination of the FANCD2 protein, which depends on a multiprotein FA core complex. In a number of patients, spontaneous genetic reversion can correct FA mutations, leading to somatic mosaicism. We analyzed the FA/BRCA pathway in 53 FA patients by FANCD2 immunoblots and chromosome breakage tests. Strikingly, FANCD2 monoubiquitination was detected in peripheral blood lymphocytes (PBLs) in 8 (15%) patients. FA reversion was further shown in these patients by comparison of primary fibro-blasts and PBLs. Reversion was associated with higher blood counts and clinical stability or improvement. Once constitutional FANCD2 patterns were determined, patients could be classified based on the level of FA/BRCA pathway disruption, as “FA core” (upstream inactivation; n = 47, 89%), FA-D2 (n = 4, 8%), and an unidentified downstream group (n = 2, 4%). FA-D2 and unidentified group patients were therefore relatively common, and they had more severe congenital phenotypes. These results show that specific analysis of the FA/BRCA pathway, combined with clinical and chromosome breakage data, allows a comprehensive characterization of FA patients.

scholarly journals End-resection at DNA double-strand breaks in the three domains of life

2013 ◽  
Vol 41 (1) ◽  
pp. 314-320 ◽  
Author(s):  
John K. Blackwood ◽  
Neil J. Rzechorzek ◽  
Sian M. Bray ◽  
Joseph D. Maman ◽  
Luca Pellegrini ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Strand Break ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Homologous Chromosomes ◽  
Domains Of Life ◽  
Strand Invasion ◽  
End Resection

During DNA repair by HR (homologous recombination), the ends of a DNA DSB (double-strand break) must be resected to generate single-stranded tails, which are required for strand invasion and exchange with homologous chromosomes. This 5′–3′ end-resection of the DNA duplex is an essential process, conserved across all three domains of life: the bacteria, eukaryota and archaea. In the present review, we examine the numerous and redundant helicase and nuclease systems that function as the enzymatic analogues for this crucial process in the three major phylogenetic divisions.

scholarly journals Cytogenetic diepoxybutane sensitivity in Serbian children with Fanconi anemia

2006 ◽  
Vol 58 (4) ◽  
pp. 215-219
Author(s):  
Sanja Cirkovic ◽  
Marija Guc-Scekic ◽  
Dragana Vujic ◽  
D. Micic
Keyword(s):  
Fanconi Anemia ◽  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Alkylating Agents ◽  
Chromosome Breakage ◽  
Child Health Care ◽  
Bone Marrow Failure Syndromes ◽  
Mother And Child Health ◽  
Mother And Child ◽  
And Child Health

Fanconi anemia (FA) is an inherited disorder with aplastic anemia, cancer susceptibility, and hypersensitivity to alkylating agents such as diepoxybutane (DEB). The DEB test is used to screen for FA among patients with bone marrow failure syndromes (BMFS). From February of 2004 to May of 2006, 29 children with BMFS were diagnosed and treated at the Mother and Child Health Care Institute of Serbia (MCHIS). In the examined group, five out of 29 patients (17.2%) were found to have increased DEB-induced chromosome breakage (0.58-2.15 vs. 0.00-0.20 breaks/cell; p<0.001) with no overlap. Our results suggest the importance of this analysis for differential diagnosis and adequate therapy of FA among patients with BMFS.

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