Nature Reviews Molecular Cell Biology

The major pathways of DNA double-strand break (DSB) repair are crucial for maintaining genomic stability. However, if deployed in an inappropriate cellular context, these same repair functions can mediate chromosome rearrangements that underlie various human diseases, ranging from developmental disorders to cancer. The two major mechanisms of DSB repair in mammalian cells are non-homologous end joining (NHEJ) and homologous recombination. In this Review, we consider DSB repair-pathway choice in somatic mammalian cells as a series of ‘decision trees’, and explore how defective pathway choice can lead to genomic instability. Stalled, collapsed or broken DNA replication forks present a distinctive challenge to the DSB repair system. Emerging evidence suggests that the ‘rules’ governing repair-pathway choice at stalled replication forks differ from those at replication-independent DSBs. The choice between the major DNA double-strand break repair pathways is important for maintaining genomic stability. In mammals, selecting one pathway over another involves a complex series of binary ‘decisions’. Emerging evidence suggests that the ‘decision tree’ governing repair-pathway choice at stalled replication forks differs from that of replication-independent double-strand breaks.

DNA double-strand break repair-pathway choice in somatic mammalian cells