ADP-ribosylation and Neurological Disease

Chromosomal DNA single-strand breaks (SSBs) are amongst the most frequent DNA lesions arising in cells and if not repaired correctly can threaten both genetic stability and cell survival. Moreover, single-strand break repair (SSBR) defects are associated with hereditary neurological disease in humans. This is illustrated by the cerebellar ataxia and seizure syndromes in which enzymatic components of the DNA end processing step of SSBR are mutated, such as ataxia oculomotor apraxia-1 (AOA1;mutated in APTX), spinocerebellar ataxia with axonal neuropathy-1 (SCAN1;mutated in TDP1), microcephaly with early-onset seizures (MCSZ; mutated in PNKP),ataxia oculomotor apraxia-4 (AOA4; mutated in PNKP), and spinocerebellar ataxia recessive type 26 (SCAR26; mutated in XRCC1). The recruitment of DNA end processing factors to sites of chromosomal SSBs is regulated in part by protein ADP-ribosylation; a process that promotes efficient SSBR but which, if SSBR is attenuated, can trigger neuropathological disease. Here, I will describe recent published and unpublished data from our laboratory addressing the role and consequences of PARP-dependent ADP-ribosylation in DNA repair and disease.