complex, giving local pulses of dNTPs at the
Such an S-phase chromosome feedback
system could also explain temporal program-
ming 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 progres-
sion 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 inte-
gral process without altering either the num-
ber 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 ap-
pears 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
). This model also explains why Mec1
(via Rad53) is a negative regulator of late-
origin firing in unchallenged cells (
predicts that a
mutant should exhibit
longer than normal S phase despite its early
firing of late origins because of its inability to
promote fork progression through
observe exactly this effect in both mitosis and
meiosis (supporting online text).
Throughout the mitotic and meiotic pro-
grams, 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
otic prophase (
), and in the cytoplasm,
where ATM mediates signal transduction dur-
ing normal cellular responses (
). Failure to
carry out certain of these basic roles then con-
tributes to the defects observed in the corre-
sponding mutants in the absence of exogenous
insult. By this view, DNA damage/replication
checkpoint responses could represent special-
ized amplifications and applications of func-
tions having more basic roles.
References and Notes
1. R. Abraham,
, 2177 (2001).
2. B. B. Zhou, S. J. Elledge,
, 433 (2000).
3. X. Zhao, A. Chabes, V. Domkin, L. Thelander, R. Roth-
, 3544 (2001).
4. B. Desany, A. A. Alcasabas, J. B. Bachant, S. J. Elledge,
, 2956 (1998).
5. Y. Xu, D. Baltimore,
, 2401 (1996).
6. B. Baker, A. Carpenter,
, 255 (1972).
7. J. M. Grushcow, T. M. Holzen, K. J. Park, T. Weintert,
M. Licheten, D. K. Bishop,
, 607 (1999).
8. K. Shirahige
, 613 (1998).
9. K. Hennessy, A. Lee, E. Chen, D. Botstein,