SSBR

Single-Strand Break Repair (SSBR) is a cellular DNA repair pathway that detects and fixes breaks in one strand of the DNA double helix. SSBs arise from oxidative stress, alkylation, replication stress, or ionizing radiation, and if left unrepaired they can block transcription or stall replication, potentially leading to more harmful double-strand breaks.

The repair process is initiated by sensing breaks with the enzyme PARP1 (and PARP2 in some contexts). Activated PARP1 recruits XRCC1, which serves as a scaffold to assemble the core repair factors. DNA polymerase beta (POLB) fills short gaps, while DNA ligase III, in complex with XRCC1, seals the nick. End-processing enzymes such as PNKP, aprataxin (APTX), and TDP1 modify 3' and 5' termini to generate ligatable ends. SSBR is closely linked to base excision repair, and many SSBs from BER intermediates are processed through the SSBR pathway.

In addition to its direct repair role, SSBR helps maintain genome stability during replication; unresolved SSBs can convert to double-strand breaks when replication forks collide with them. The pathway is regulated by intricate signaling networks, including PARP1-mediated chromatin remodeling and recruitment of repair proteins.

Clinical relevance is highlighted by the link between SSBR defects and disease. Mutations in SSBR components have been associated with neurodegenerative disorders and cancer predisposition. Examples include mutations in APTX (ataxia with oculomotor apraxia type 1) and PNKP (microcephaly with seizures), with XRCC1 variants also reported in cancer risk studies. PARP inhibitors exploit SSBR defects in BRCA-mutant cancers, illustrating the therapeutic relevance of this pathway.