Genome maintenance mechanisms for preventing cancer

Hoeijmakers, Jan H.J.

doi:10.1038/35077232

Cited by 3,468 publications

(2,748 citation statements)

References 61 publications

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“…The efficient repair of DNA damage is crucial for chromosome integrity, since it prevents mutations, chromosomal aberrations and errors in essential processes such as transcription, replication and chromosome segregation (Hoeijmakers, 2001). One of the key mechanisms for repairing DNA double‐strand breaks (DSBs) is homologous recombination (HR).…”

Section: Introductionmentioning

confidence: 99%

Two distinct conformational states define the interaction of human RAD 51‐ ATP with single‐stranded DNA

et al. 2018

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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.

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Section: Introductionmentioning

confidence: 99%

Two distinct conformational states define the interaction of human RAD 51‐ ATP with single‐stranded DNA

et al. 2018

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“…Telomeres are repetitive noncoding DNA sequences found at the ends of eukaryotic chromosomes that play an important role in genome stability (Hoeijmakers, 2001). They shorten largely as a consequence of loss during cell division.…”

Section: Introductionmentioning

confidence: 99%

Brood size moderates associations between relative size, telomere length, and immune development in European starling nestlings

Nettle

Andrews

Reichert

et al. 2016

Ecology and Evolution

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For young birds in a nest, body size may have implications for other aspects of development such as telomere length and immune function. However, it is possible to predict associations in either direction. On the one hand, there may be trade‐offs between growth and telomere maintenance, and growth and investment in immune function, suggesting there will be negative correlations. On the other hand, relatively larger individuals might be advantaged in competition with their nest‐mates, allowing them to garner more resources overall, leading to positive correlations. We studied development over the nestling period in 34 nests of wild European starlings, Sturnus vulgaris. Intrabrood competition is typically more intense in larger broods. Hence, we predicted that body size should become an increasingly positive predictor of telomere length and immune functioning as brood size increases. In partial support of our prediction, there were significant interactions between brood size and body size in predicting both erythrocyte telomere length change and plasma levels of the cytokine interleukin‐6. The associations between body size and these outcomes went from negative in the smallest broods to positive in the largest. A further immune marker, high‐sensitivity C‐reactive protein, showed no systematic patterning with body size or brood size. Our results confirm that the size to which a nestling grows is important for telomere dynamics and the development of the immune system, but the phenotypic associations are moderated by the competitive context.

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“…Critical surveillance of this transmission is provided by the DNA damage response (Zhou and Elledge, 2000). Disruption or attenuation of this response plays an essential role in promoting tumorigenesis (Lengauer et al, 1998;Hoeijmakers, 2001;Schar, 2001;Rouse and Jackson, 2002). Stalled replication forks are sensed by replication protein A (RPA)-mediated ATR (ATM-and Rad3-related kinase) recruitment to DNA damage-induced nuclear foci (Zou and Elledge, 2003).…”

Section: Introductionmentioning

confidence: 99%

ERK activity facilitates activation of the S-phase DNA damage checkpoint by modulating ATR function

Chen

Parihar

et al. 2005

Oncogene

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Although Erk kinase has been recently reported to function in the DNA damage response, the mechanism governing this process is unknown. We report here that hydroxyurea (HU) activates Erk via MEK1, a process that is sensitized by a constitutively active MEK1 (MEK1Q56P) and attenuated by a dominant-negative MEK1 (MEK1K97M). While ectopic MEK1Q56P sensitized HU-induced S-phase arrest, inhibition of Erk activation via U0126, PD98059, and MEK1K97M attenuated the arrest, and thereby enhanced cells to HU-induced toxicity. Taken together, we demonstrate an important contribution of Erk to the activation of the S-phase DNA damage checkpoint. This can be attributed to Erk's regulatory role in modulating ATR function. Inhibition of Erk activation with U0126/PD98059 and MEK1K97M substantially reduced HU-induced ATR nuclear foci, leading to a dramatic reduction of cH2AX and its nuclear foci. Reduction of MEK1 function by a small interference RNA (siRNA) MEK1 and ectopic MEK1K97M significantly decreased HU-induced cH2AX. Conversely, ectopic MEK1Q56P enhanced cH2AX foci. Furthermore, immunofluorescent and cell fractioning experiments revealed cytosolic and nuclear localization of ATR. HU treatment caused the redistribution of ATR from the cytosol to the nucleus, a process that is inhibited by U0126. Collectively, we show that Erk kinase modulates HU-initiated DNA damage response by regulating ATR function.

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Genome maintenance mechanisms for preventing cancer

Cited by 3,468 publications

References 61 publications

Two distinct conformational states define the interaction of human RAD 51‐ ATP with single‐stranded DNA

Two distinct conformational states define the interaction of human RAD 51‐ ATP with single‐stranded DNA

Brood size moderates associations between relative size, telomere length, and immune development in European starling nestlings

ERK activity facilitates activation of the S-phase DNA damage checkpoint by modulating ATR function

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