Fragile Sites on Human Chromosomes

Abstract

complex, giving local pulses of dNTPs at the appropriate times. Such an S-phase chromosome feedback system could also explain temporal programming and modulation of S-phase length. Mec1 may act in cis to promote replication fork progression and in trans to inhibit late replication origin firing as well as S-phase exit. If Mec1-mediated fork progression were accompanied by coordinate alleviation of the two trans inhibitory effects, orderly progression of replication and post-fork development throughout the genome could be ensured; once all forks are resolved, the cell would exit S phase. Moreover, the length of S phase could be expanded or contracted as an integral process without altering either the number or the pattern of fired origins or the intrinsic rate of fork progression. Instead, the length of S phase could be governed by the rate of post-fork chromosome morphogene-sis. Correspondingly, meiotic S phase appears to be an expanded version of mitotic S phase, and its length is modulated positively by meiotic cohesin Rec8 and negatively by meiotic pairing/recombination protein Spo11 (28). This model also explains why Mec1 (via Rad53) is a negative regulator of late-origin firing in unchallenged cells (8) and predicts that a rad53 mutant should exhibit longer than normal S phase despite its early firing of late origins because of its inability to promote fork progression through RSZs. We observe exactly this effect in both mitosis and meiosis (supporting online text). Throughout the mitotic and meiotic programs , chromosomal changes must occur in a regulated way throughout the genome, different chromosomal events must be coordinated with one another, and progression of the cell cycle must be linked to proper completion of such processes. We suggest that ATR/ATM-family proteins mediate such effects, not only during S phase but also potentially during G 1 (5), mei-otic prophase (6, 7), and in the cytoplasm, where ATM mediates signal transduction during normal cellular responses (29). Failure to carry out certain of these basic roles then contributes to the defects observed in the corresponding mutants in the absence of exogenous insult. By this view, DNA damage/replication checkpoint responses could represent specialized amplifications and applications of functions having more basic roles.