Single-strand break repair and genetic disease

Abstract

Single-strand breaks (SSBs) are the most common lesions arising in cells, and chromosomal single-strand break repair (SSBR) is a rapid and efficient process. In addition to the rapid 'global' SSBR processes that remove SSBs throughout the genome and throughout interphase, there might be S-phase specific processes that operate at replication forks in conjunction with homologous recombination. Two of the proteins that repair damaged DNA termini during global SSBR (tyrosyl-DNA phosphodiesterase 1 and aprataxin) are mutated in the hereditary genetic diseases spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) and ataxia oculomotor apraxia 1 (AOA1), implicating unrepaired SSBs in progressive neurological dysfunction. Whereas post-mitotic cells seem to be dependent on global SSBR for genetic integrity, proliferating cells can additionally use replication-coupled SSBR. This might explain why SCAN1 and AOA1 are not associated with elevated genetic instability and cancer.