Constitutive DNA damage is linked to DNA replication abnormalities in Bloom's syndrome cells.

Abstract:

:Bloom's syndrome (BS) is an autosomal recessive disorder associated with an elevated incidence of cancers. The gene mutated in BS, BLM, encodes a RecQ helicase family member. BS cells exhibit genomic instability, including excessive homologous recombination and chromosomal aberrations. We reported previously that BS cells also demonstrate increased error-prone nonhomologous endjoining, which could contribute to genomic instability in these cells. Here, we show that BS cells display an abnormality in the timing of replication of both early-replicating genes and late-replicating loci such as chromosomal fragile sites. This delayed replication is associated with a constitutively increased frequency of sites of DNA damage and repair, as determined by the presence of DNA repair factors such as RAD51 and Ku86. In addition, another RecQ family helicase, WRN, also localizes to these repair sites. The presence of these repair sites correlates with the temporal appearance of cyclin B1 expression, indicative of the cells having progressed beyond mid-S phase in the cell division cycle. Critically, these defects in BS cells are the direct result of loss of BLM function, because BS cells phenotypically 'reverted' following transfection with the BLM cDNA no longer show such defects. Thus, our data indicate that constitutive DNA damage is coupled to delayed DNA replication in BS cells.

journal_name

Oncogene

journal_title

Oncogene

authors

Rassool FV,North PS,Mufti GJ,Hickson ID

doi

10.1038/sj.onc.1206970

subject

Has Abstract

pub_date

2003-11-27 00:00:00

pages

8749-57

issue

54

eissn

0950-9232

issn

1476-5594

pii

1206970

journal_volume

22

pub_type

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