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1.
Peter M. Glazer Denise C. Hegan Yuhong Lu Jennifer Czochor Susan E. Scanlon 《The Yale journal of biology and medicine》2013,86(4):443-451
Hypoxia is a characteristic feature of solid tumors and occurs very early in
neoplastic development. Hypoxia transforms cell physiology in multiple ways,
with profound changes in cell metabolism, cell growth, susceptibility to
apoptosis, induction of angiogenesis, and increased motility. Over the past 20
years, our lab has determined that hypoxia also induces genetic instability. We
have conducted a large series of experiments revealing that this instability
occurs through the alteration of DNA repair pathways, including nucleotide
excision repair, DNA mismatch repair, and homology dependent repair. Our work
suggests that hypoxia, as a key component of solid tumors, can drive cancer
progression through its impact on genomic integrity. However, the acquired
changes in DNA repair that are induced by hypoxia may also render hypoxic cancer
cells vulnerable to tailored strategies designed to exploit these changes. 相似文献
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Philip C. Hanawalt 《The Yale journal of biology and medicine》2013,86(4):517-523
As a graduate student with Professor Richard Setlow at Yale in the late 1950s, I
studied the effects of ultraviolet and visible light on the syntheses of DNA,
RNA, and protein in bacteria. I reflect upon my research in the Yale Biophysics
Department, my subsequent postdoctoral experiences, and the eventual analyses in
the laboratories of Setlow, Paul Howard-Flanders, and myself that constituted
the discovery of the ubiquitous pathway of DNA excision repair in the early
1960s. I then offer a brief perspective on a few more recent developments in the
burgeoning DNA repair field and their relationships to human disease. 相似文献
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Cellular DNA damage response is critical to preserving genomic integrity
following exposure to genotoxic stress. A complex series of networks and
signaling pathways become activated after DNA damage and trigger the appropriate
cellular response, including cell cycle arrest, DNA repair, and apoptosis. The
response elicited is dependent upon the type and extent of damage sustained,
with the ultimate goal of preventing propagation of the damaged DNA. A major
focus of our studies is to determine the cellular pathways involved in
processing damage induced by altered helical structures, specifically triplexes.
Our lab has demonstrated that the TFIIH factor XPD occupies a central role in
triggering apoptosis in response to triplex-induced DNA strand breaks. We have
shown that XPD co-localizes with γH2AX, and its presence is required for the
phosphorylation of H2AX tyrosine142, which stimulates the signaling pathway to
recruit pro-apoptotic factors to the damage site. Herein, we examine the
cellular pathways activated in response to triplex formation and discuss our
finding that suggests that XPD-dependent apoptosis plays a role in preserving
genomic integrity in the presence of excessive structurally induced DNA
damage. 相似文献
4.
James M. Daley YoungHo Kwon Hengyao Niu Patrick Sung 《The Yale journal of biology and medicine》2013,86(4):453-461
The DNA double-strand break (DSB), arising from exposure to ionizing radiation or
various chemotherapeutic agents or from replication fork collapse, is among the
most dangerous of chromosomal lesions. DSBs are highly cytotoxic and can lead to
translocations, deletions, duplications, or mutations if mishandled. DSBs are
eliminated by either homologous recombination (HR), which uses a homologous
template to guide accurate repair, or by nonhomologous end joining (NHEJ), which
simply rejoins the two broken ends after damaged nucleotides have been removed.
HR generates error-free repair products and is also required for generating
chromosome arm crossovers between homologous chromosomes in meiotic cells. The
HR reaction includes several distinct steps: resection of DNA ends, homologous
DNA pairing, DNA synthesis, and processing of HR intermediates. Each occurs in a
highly regulated fashion utilizing multiple protein factors. These steps are
being elucidated using a combination of genetic tools, cell-based assays, and
in vitro reconstitution with highly purified HR proteins.
In this review, we summarize contributions from our laboratory at Yale
University in understanding HR mechanisms in eukaryotic cells. 相似文献
5.
W. Dean Rupp 《The Yale journal of biology and medicine》2013,86(4):499-505
The discovery of nucleotide excision repair in 1964 showed that DNA could berepaired by a mechanism that removed the damaged section of a strand andreplaced it accurately by using the remaining intact strand as the template.This result showed that DNA could be actively metabolized in a process that hadno precedent. In 1968, experiments describing postreplication repair, a processdependent on homologous recombination, were reported. The authors of thesepapers were either at Yale University or had prior Yale connections. Here werecount some of the events leading to these discoveries and consider the impacton further research at Yale and elsewhere. 相似文献
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Gary M. Kupfer 《The Yale journal of biology and medicine》2013,86(4):491-497
Fanconi anemia (FA) is a fascinating, rare genetic disorder marked by congenital
defects, bone marrow failure, and cancer susceptibility. Research in recent
years has led to the elucidation of FA as a DNA repair disorder and involved
multiple pathways as well as having wide applicability to common cancers,
including breast, ovarian, and head and neck. This review will describe the
clinical aspects of FA as well as the current state of its molecular
pathophysiology. In particular, work from the Kupfer laboratory will be
described that demonstrates how the FA pathway interacts with multiple DNA
repair pathways, including the mismatch repair system and signal transduction
pathway of the DNA damage response. 相似文献
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Sreerupa Ray Miriam Rose Menezes Alireza Senejani Joann B. Sweasy 《The Yale journal of biology and medicine》2013,86(4):463-469
Since its discovery and purification in 1971, DNA polymerase ß (Pol ß) is one of
the most well-studied DNA polymerases. Pol ß is a key enzyme in the base
excision repair (BER) pathway that functions in gap filling DNA synthesis
subsequent to the excision of damaged DNA bases. A major focus of our studies is
on the cellular roles of Pol ß. We have shown that germline and tumor-associated
variants of Pol ß catalyze aberrant BER that leads to genomic instability and
cellular transformation. Our studies suggest that Pol ß is critical for the
maintenance of genomic stability and that it is a tumor suppressor. We have also
shown that Pol ß functions during Prophase I of meiosis. Pol ß localizes to the
synaptonemal complex and is critical for removal of the Spo11 complex from the
5’ ends of double-strand breaks. Studies with Pol ß mutant mice are currently
being undertaken to more clearly understand the function of Pol ß during
meiosis. In this review, we will highlight our contributions from our studies of
Pol ß germline and cancer-associated variants. 相似文献
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Antony W Oliver Sally Swift Christopher J Lord Alan Ashworth Laurence H Pearl 《EMBO reports》2009,10(9):990-996
The breast cancer 2, early onset protein (BRCA2) is central to the repair of DNA damage by homologous recombination. BRCA2 recruits the recombinase RAD51 to sites of damage, regulates its assembly into nucleoprotein filaments and thereby promotes homologous recombination. Localization of BRCA2 to nuclear foci requires its association with the partner and localizer of BRCA2 (PALB2), mutations in which are associated with cancer predisposition, as well as subtype N of Fanconi anaemia. We have determined the structure of the PALB2 carboxy‐terminal β‐propeller domain in complex with a BRCA2 peptide. The structure shows the molecular determinants of this important protein–protein interaction and explains the effects of both cancer‐associated truncating mutants in PALB2 and missense mutations in the amino‐terminal region of BRCA2. 相似文献
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Two distinct conformational states define the interaction of human RAD51‐ATP with single‐stranded DNA 下载免费PDF全文
Andrea Candelli Edwige B Garcin Mauro Modesti Luca Pellegrini Gijs JL Wuite Erwin JG Peterman 《The EMBO journal》2018,37(7)
An essential mechanism for repairing DNA double‐strand breaks is homologous recombination (HR). One of its core catalysts is human RAD51 (hRAD51), which assembles as a helical nucleoprotein filament on single‐stranded DNA, promoting DNA‐strand exchange. Here, we study the interaction of hRAD51 with single‐stranded DNA using a single‐molecule approach. We show that ATP‐bound hRAD51 filaments can exist in two different states with different contour lengths and with a free‐energy difference of ~4 kBT per hRAD51 monomer. Upon ATP hydrolysis, the filaments convert into a disassembly‐competent ADP‐bound configuration. In agreement with the single‐molecule analysis, we demonstrate the presence of two distinct protomer interfaces in the crystal structure of a hRAD51‐ATP filament, providing a structural basis for the two conformational states of the filament. Together, our findings provide evidence that hRAD51‐ATP filaments can exist in two interconvertible conformational states, which might be functionally relevant for DNA homology recognition and strand exchange. 相似文献
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Brough R Bajrami I Vatcheva R Natrajan R Reis-Filho JS Lord CJ Ashworth A 《The EMBO journal》2012,31(5):1160-1176
Mutations in BRCA2 confer an increased risk of cancer development, at least in part because the BRCA2 protein is required for the maintenance of genomic integrity. Here, we use proteomic profiling to identify APRIN (PDS5B), a cohesion-associated protein, as a BRCA2-associated protein. After exposure of cells to hydroxyurea or aphidicolin, APRIN and other cohesin components associate with BRCA2 in early S-phase. We demonstrate that APRIN expression is required for the normal response to DNA-damaging agents, the nuclear localisation of RAD51 and BRCA2 and efficient homologous recombination. The clinical significance of these findings is indicated by the observation that the BRCA2/APRIN interaction is compromised by BRCA2 missense variants of previously unknown significance and that APRIN expression levels are associated with histological grade in breast cancer and the outcome of breast cancer patients treated with DNA-damaging chemotherapy. 相似文献
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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。 相似文献
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The partner and localizer of breast cancer 2 susceptibility protein (PALB2) is crucial for the repair of DNA damage by homologous recombination. Here, we report that chromatin-association motif (ChAM), an evolutionarily conserved motif in PALB2, is necessary and sufficient to mediate its chromatin association in both unperturbed and damaged cells. ChAM is distinct from the previously described PALB2 DNA-binding regions. Deletion of ChAM decreases PALB2 and Rad51 accumulation at DNA damage sites and confers cellular hypersensitivity to the genotoxic drug mitomycin C. These results suggest that PALB2 chromatin association via ChAM facilitates PALB2 function in the cellular resistance to DNA damage. 相似文献
20.
《DNA Repair》2014
Brh2, the BRCA2 ortholog in the fungus Ustilago maydis, harbors two different DNA-binding domains, one located in the N-terminal region and the other located in the C-terminal region. Here we were interested in comparing the biochemical properties of Brh2 fragments, Brh2NT and Brh2CT, respectively, harboring the two different DNA-binding regions to understand the mechanistic purpose of dual DNA-interaction domains. With oligonucleotide substrates to model different DNA conformations, it was found that the substrate specificity of Brh2NT and Brh2CT was almost indistinguishable although avidity was different depending on salt concentration. DNA annealing activity inherent in Brh2 was found to be attributable to Brh2NT. Likewise, activity responsible for a second-end capture reaction modeling a later step in repair of DNA double-strand breaks was found attributable to Brh2NT. Efficient annealing of DNA strands coated with RPA required full length Brh2 rather than Brh2NT suggesting Brh2CT contributes to the activity when RPA is present. Brh2NT and Brh2CT were both found capable of physically interacting with RPA. The results suggest that while the two DNA-binding regions of Brh2 appear functionally redundant in certain aspects of DNA repair, they differ in fundamental properties, and likely contribute in different ways to repair processes involving or arising from stalled DNA replication forks. 相似文献