RPA4 is a primate-specific alternative replication protein A subunit that forms a distinct single-stranded DNA-binding complex with RPA1 and RPA3 1. Unlike canonical RPA (containing RPA2), alternative-RPA (aRPA) containing RPA4 binds ssDNA with high affinity but cannot support chrX DNA replication or S-phase progression 2. Instead, aRPA localizes to DNA repair sites and supports nucleotide excision repair and homologous recombination processes 2. RPA4 is preferentially expressed in placental and colon tissues, with abundant expression in nonproliferative tissues 1. Mechanistically, aRPA inhibits canonical RPA function through its L34 loop and C-terminal regions, potentially preventing proliferation in quiescent cells 3. In disease contexts, aRPA antagonizes canonical RPA's protective effects against CAG repeat expansions associated with Huntington disease and spinocerebellar ataxia 4. Overexpression of canonical RPA in SCA1 brains eliminates expansions and improves neurological outcomes, while aRPA promotes expansions 4. These findings suggest RPA4 functions as a regulatory switch, suppressing replication while maintaining genome stability in nonproliferative tissues, with pathological implications for trinucleotide repeat disorders.