Mammalian TIMELESS and Tipin are Evolutionarily Conserved Replication Fork-associated Factors

摘要: Abstract The function of the mammalian TIMELESS protein (TIM) has been enigmatic. TIM is essential for early embryonic development, but little known regarding its biochemical and cellular function. Although identified based on similarity to a Drosophila circadian clock factor, it also shares with second family proteins that more widely conserved throughout eukaryotes. Members this in yeast (S.c. Tof1p, S.p. Swi1p) have implicated DNA synthesis, S-phase-dependent checkpoint activation chromosome cohesion, three processes coordinated at level replication fork complex. present work demonstrates constitutive binding partner, Tipin (ortholog S.c. Csm3p, Swi3p), are replisome-associated proteins. Both associate components endogenous complex, BrdU-positive sites. Knock-down compromises efficiency. Further, direct TIM-Tipin complex 34 kDa subunit A provides explanation potential coupling role these Like TIM, involved molecular mechanism UV-dependent cell growth arrest. additionally associates peroxiredoxin2 appears be responses H2O2, recently described versions Tipin. Together, establishes as functional orthologs their counterparts capable coordinating genotoxic stress responses, distinguishes from circadian-specific paralogs which was originally identified.