Abstract
Aberrant DNA replication is a primary cause of mutations that are associated with pathological disorders including cancer. During DNA metabolism, the primary causes of replication fork stalling include secondary DNA structures, highly transcribed regions and damaged DNA. The restart of stalled replication forks is critical for the timely progression of the cell cycle and ultimately for the maintenance of genomic stability. Our previous work has implicated the single-stranded DNA binding protein, hSSB1/NABP2, in the repair of DNA double-strand breaks via homologous recombination. Here, we demonstrate that hSSB1 relocates to hydroxyurea (HU)-damaged replication forks where it is required for ATR and Chk1 activation and recruitment of Mre11 and Rad51. Consequently, hSSB1-depleted cells fail to repair and restart stalled replication forks. hSSB1 deficiency causes accumulation of DNA strand breaks and results in chromosome aberrations observed in mitosis, ultimately resulting in hSSB1 being required for survival to HU and camptothecin. Overall, our findings demonstrate the importance of hSSB1 in maintaining and repairing DNA replication forks and for overall genomic stability.
Highlights
The DNA damage response is a crucial component of the surveillance network that maintains the stability and integrity of the genome
HSSB1-deicient human cells and hSSB1 knockout mouse bone-marrow cells show spontaneous generation of DNA double-strand breaks (DSBs) that are most likely generated by the collapse of DNA replication forks and their incorrect repair [18,28]
Since the hypersensitivity of hSSB1-depleted cells to agents that damage replication forks suggests that hSSB1 may be required to repair DNA damage at replication forks, we investigated whether hSSB1 was recruited to stalled replication forks
Summary
The DNA damage response is a crucial component of the surveillance network that maintains the stability and integrity of the genome. In order for genomic integrity to be maintained, faithful DNA replication is essential. Defects in the pathways involved in the recovery and stabilisation of stalled replication forks lead to genomic instability and chromosomal rearrangements, both of which are key hallmarks of cancer cells [2]. This highlights the importance of characterizing proteins and pathways involved in repair of stalled replication forks
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