Trichothiodystrophy and the relationship between DNA repair and cancer

The identification of cellular deficiencies in the ability to repair damage in DNA in individuals with several cancer-prone genetic disorders, has led to the idea that defective DNA repair results in cancer. In patients with trichothiodystrophy, however, a recently discovered defect in the repair of ultraviolet damage in DNA is not associated with cancer-proneness. Thus our previous ideas about the connections between DNA repair capacity and cancer susceptibility need to be reevaluated.     

The XRCC genes: expanding roles in DNA double-strand break repair

Functional analysis of the XRCC genes continues to make an important contribution to the understanding of mammalian DNA double-strand break repair processes and mechanisms of genetic instability leading to cancer. New data implicate XRCC genes in long-standing questions, such as how homologous recombination (HR) intermediates are resolved and how DNA replication slows in the presence of damage (intra-S checkpoint). Examining the functions of XRCC genes involved in non-homologous end joining (NHEJ), paradoxical roles in repair fidelity and telomere maintenance have been found. Thus, XRCC5-7 (DNA-PK)-dependent NHEJ commonly occurs with fidelity, perhaps by aligning ends accurately in the absence of sequence microhomologies, but NHEJ-deficient mice show reduced frequencies of mutation. NHEJ activity seems to be involved in both mitigating and mediating telomere fusions; however, defective NHEJ can lead to telomere elongation, while loss of HR activity leads to telomere shortening. The correct functioning of XRCC genes involved in both HR and NHEJ is important for genetic stability, but loss of each pathway leads to different consequences, with defects in HR additionally leading to mitotic disruption and aneuploidy. Confirmation that these responses are likely to contribute to cancer induction and/or progression, is given by studies of humans and mice with XRCC gene disruptions: those affecting NHEJ show increased lymphoid tumours, while those affecting HR lead to breast cancer and perhaps to gynaecological tumours.     

The mammalian XRCC genes: their roles in DNA repair and genetic stability

Analysis of the XRCC genes has played an important part in understanding mammalian DNA repair processes, especially those involved in double-strand break (DSB) repair. Most of these genes were identified through their ability to correct DNA damage hypersensitivity in rodent cell lines, and they represent components of several different repair pathways including base-excision repair, non-homologous end joining, and homologous recombination. We document the phenotypic effects of mutation of the XRCC genes, and the current state of our knowledge of their functions. In addition to their continuing importance in discovering mechanisms of DNA repair, analysis of the XRCC genes is making a substantial contribution to the understanding of specific human disorders, including cancer.     

Multiple roles of vertebrate REV genes in DNA repair and recombination

In yeast, Rev1, Rev3, and Rev7 are involved in translesion synthesis over various kinds of DNA damage and spontaneous and UV-induced mutagenesis. Here, we disrupted Rev1, Rev3, and Rev7 in the chicken B-lymphocyte line DT40. REV1-/- REV3-/- REV7-/- cells showed spontaneous cell death, chromosomal instability/fragility, and hypersensitivity to various genotoxic treatments as observed in each of the single mutants. Surprisingly, the triple-knockout cells showed a suppressed level of sister chromatid exchanges (SCEs), which may reflect postreplication repair events mediated by homologous recombination, while each single mutant showed an elevated SCE level. Furthermore, REV1-/- cells as well as triple mutants showed a decreased level of immunoglobulin gene conversion, suggesting participation of Rev1 in a recombination-based pathway. The present study gives us a new insight into cooperative function of three Rev molecules and the Polzeta (Rev3-Rev7)-independent role of Rev1 in vertebrate cells.     

Untangling the crosstalk between BRCA1 and R-loops during DNA repair

R-loops are RNA:DNA hybrids assembled during biological processes but are also linked to genetic instability when formed out of their natural context. Emerging evidence suggests that the repair of DNA double-strand breaks requires the formation of a transient R-loop, which eventually must be removed to guarantee a correct repair process. The multifaceted BRCA1 protein has been shown to be recruited at this specific break-induced R-loop, and it facilitates mechanisms in order to regulate R-loop removal. In this review, we discuss the different potential roles of BRCA1 in R-loop homeostasis during DNA repair and how these processes ensure faithful DSB repair.     

Assessment of the relationship between combinations of polymorphic variants of xenobiotic-metabolizing enzyme genes and predisposition to lung cancer

An imbalance between the phases of biotransformation systems, such as activation, detoxification, and release of toxic substances, is one of the causes of multifactor pathology. Therefore, it is important to examine the impact of the total contribution of the polymorphic variants of xenobiotic-metabolizing enzyme genes at all three phases on predisposition to lung cancer. The purposes of the present work were to study the relationship between polymorphic variants of xenobiotic-metabolizing enzyme genes and risk of lung cancer and to identify molecular genetic markers of predisposition to the disease. It was shown that GSTT1 null-genotype plays a dominant role in the development of lung cancer predisposition in the Belarusian population, while the polymorphic variants of other genes of xenobiotic-metabolizing enzymes render a modifying effect on predisposition to this disease. Combination 734AA CYP1A2/GSTT1(?)/GSTM1(+)/“slow” acetylator has the greatest risk significance, and combination GSTT1(?)/GSTM1(+)/“slow” acetylator exerts a protective effect.     

乳腺癌易感蛋白1在DNA损伤修复中的作用

人类乳腺癌易感基因1(breast cancer susceptibility gene 1,BRCA1)首先是在乳腺癌家族中发现的,是具有遗传倾向的乳腺癌和卵巢癌易感基因,其基因的突变与家族性乳腺癌及卵巢癌的发生有密切联系。BRCA1是一种抑癌基因,其基因产物可以参与维持基因组稳定性的多条细胞信号通路,例如DNA损伤诱导的细胞周期调控、DNA损伤修复、基因转录调节、细胞凋亡、泛素化等重要的细胞活动。本文就近几年来BRCA1在DNA损伤修复中的作用的研究进展作一综述,包括DNA损伤诱导的细胞周期检查点的激活和DNA损伤修复两方面。     

BRCA1和BRCA2与DNA损伤修复及转录调控

乳腺癌和卵巢癌敏感基因BRCA1和BRCA2与同源重组,DNA损伤修复,胚胎生长,转录调控及遍在蛋白化有关,其中,BRCA1和BRCA2在DNA损伤修复和转录调控中功能的确定,将有助于探讨和阐明两者的肿瘤抑制功能及其机理,作者将综述近年来有关BRCA1和BRCA2在DNA损伤修复和转录调控中功能研究的最新进展。     

Association between DNA damage, DNA repair genes variability and clinical characteristics in breast cancer patients

The cell's susceptibility to DNA damage and its ability to repair this damage are important for cancer induction, promotion and progression. In the present work we determined the level of basal (total endogenous) and endogenous oxidative DNA damage as well as polymorphism of the DNA repair genes: RAD51 (135 G/C), XRCC3 (Thr241Met), OGG1 (Ser326Cys) and XPD (Lys751Gln) in peripheral blood lymphocytes of 41 breast cancer patients and 48 healthy individuals. DNA damage was evaluated by alkaline comet assay with DNA repair enzymes: Endo III and Fpg, preferentially recognizing oxidized DNA bases. The genotypes of the polymorphisms were determined by restriction fragment length polymorphism PCR. We observed a strong association between breast cancer occurrence and the genotypes C/C of the RAD51-135G/C polymorphism, Ser/Ser of the OGG1-Ser326Cys and Lys/Gln of the XPD-Lys751Gln, whereas the genotypes G/C of the RAD51-135G/C and Lys/Lys of the XPD-Lys751Gln exerted a protective effect against breast cancer. We also found that individuals with the G/C genotype of the RAD51-135G/C polymorphism and with the Lys/Lys genotype of the XPD-Lys751Gln polymorphism displayed a lower extent of basal and oxidative DNA damage. A strong association between higher level of oxidative DNA damage and the Lys/Gln genotype of the latter polymorphism was found. We also correlated genotypes with clinical characteristics of breast cancer patients. We observed a strong association between the G/C genotype of the RAD51-135 G/C polymorphism and the expression of the progesterone receptor and between both alleles of the OGG1-Ser326Cys polymorphism and lymph node metastasis. Our results suggest that the polymorphism of the RAD51, OGG1 and XPD genes may be linked with breast cancer by the modulation of the cellular response to oxidative stress and these polymorphisms may be considered as markers in breast cancer along with the genetic or/and environmental indicators of oxidative stress.     

BRCA1, microRNAs and cancer predisposition: Challenging the dogma

Comment on: Pelletier C, et al. Cell Cycle 2011; 10:90–1

     

Functional interplay between BRCA2/FancD1 and FancC in DNA repair

A rare hereditary disorder, Fanconi anemia (FA), is caused by mutations in an array of genes, which interact in a common FA pathway/network. These genes encode components of the FA "core" complex, a key factor FancD2, the familial breast cancer suppressor BRCA2/FancD1, and Brip1/FancJ helicase. Although BRCA2 is known to play a pivotal role in homologous recombination repair by regulating Rad51 recombinase, the precise functional relationship between BRCA2 and the other FA genes is unclear. Here we show that BRCA2-dependent chromatin loading of Rad51 after mitomycin C treatment was not compromised by disruption of FANCC or FANCD2. Rad51 and FancD2 form colocalizing subnuclear foci independently of each other. Furthermore, we created a conditional BRCA2 truncating mutation lacking the C-terminal conserved domain (CTD) (brca2DeltaCTD), and disrupted the FANCC gene in this background. The fancc/brca2DeltaCTD double mutant revealed an epistatic relationship between FANCC and BRCA2 CTD in terms of x-ray sensitivity. In contrast, levels of cisplatin sensitivity and mitomycin C-induced chromosomal aberrations were increased in fancc/brca2DeltaCTD cells relative to either single mutant. Taken together, these results indicate that FA proteins work together with BRCA2/Rad51-mediated homologous recombination in double strand break repair, whereas the FA pathway plays a role that is independent of the CTD of BRCA2 in interstrand cross-link repair. These results provide insights into the functional interplay between the classical FA pathway and BRCA2.     

Architects meets Repairers: The interplay between homeobox genes and DNA repair

Homeobox genes are widely considered the major protagonists of embryonic development and tissue formation. For the past decades, it was established that the deregulation of these genes is intimately related to developmental abnormalities and a broad range of diseases in adults. Since the proper regulation and expression of homeobox genes are necessary for a successful developmental program and tissue function, their relation to DNA repair mechanisms become a necessary discussion. However, important as it is, studies focused on the interplay between homeobox genes and DNA repair are scarce, and there is no critical discussion on the subject. Hence, in this work, I aim to provide the first review of the current knowledge of the interplay between homeobox genes and DNA repair mechanisms, and offer future perspectives on this, yet, young ground for new researches. Critical discussion is conducted, together with a careful assessment of each reviewed topic.     

The role of the BRCA1 tumor suppressor in DNA double-strand break repair

The tumor suppressor gene BRCA1 was cloned in 1994 based on its linkage to early-onset breast and ovarian cancer. Although the BRCA1 protein has been implicated in multiple cellular functions, the precise mechanism that determines its tumor suppressor activity is not defined. Currently, the emerging picture is that BRCA1 plays an important role in maintaining genomic integrity by protecting cells from double-strand breaks (DSB) that arise during DNA replication or after DNA damage. The DSB repair pathways available in mammalian cells are homologous recombination and nonhomologous end-joining. BRCA1 function seems to be regulated by specific phosphorylations in response to DNA damage and we will focus this review on the roles played by BRCA1 in DNA repair and cell cycle checkpoints. Finally, we will explore the idea that tumor suppression by BRCA1 depends on its control of DNA DSB repair, resulting in the promotion of error-free and the inhibition of error-prone recombinational repair.     

Sequence fingerprints in BRCA2 and RAD51: implications for DNA repair and cancer

In humans, the interactions between the breast cancer susceptibility protein, BRCA2, and the RAD51 recombinase are essential for DNA repair by homologous recombination (HR), failure of which can predispose to cancer. The interactions occur through conserved BRC repeat motifs, encoded in BRCA2, binding directly to RAD51. Here, we describe full and partial BRCA2 homologues from a wide range of eukaryotes, including Drosophila melanogaster and two Plasmodium species. The crystal structure of the human BRC4-RAD51 complex allows identification of residues that are important for protein-protein interaction, and defines interaction sequence fingerprints for the BRC repeat and for RAD51. These allow us to predict that most eukaryotic RAD51 and BRC repeat orthologues should be capable of mutual interactions. We find no evidence for the presence of BRC repeats in yeast, Archaea and bacteria, and their RAD51 orthologues do not fulfil the criteria for binding the BRC repeat. Similarly, human RAD51 paralogues, including RAD51B, RAD51C, RAD51D, XRCC2, XRCC3 and DMC1, are not predicted to bind the BRC repeat. Conservation of the BRC repeat and RAD51 sequence fingerprints across a wide range of eukaryotic species substantiates the functional significance of the BRCA2-RAD51 interactions. The idea of multiple BRC repeats with binding specificity towards RAD51 leads us to suggest a possible model for the participation of BRCA2 in RAD51 nucleoprotein filament formation.