Biology Reference
In-Depth Information
has been ascribed to human MutL
b
, the interactome of hPMS1 includes a
number of proteins from the ubiquitylation pathway, suggesting that the func-
tion of MutL
b
may be modulated by ubiquitylation.
60
While strand discontinuities and gaps can direct mismatch repair
in vitro
,the
mechanism of strand discrimination remains obscure (
Fig. 1
). Interestingly,
when the excision step of the mismatch repair process is reconstituted
in vitro
,
different proteins are required depending on whether the nick is positioned 5
0
or
3
0
to the mismatch. MutS
a
, the SSB protein replication protein A (RPA), and the
exonuclease Exo1 are required when the nick is located 5
0
to the mis-
match.
50,61,62
In addition to these factors, MutL
a
, the proliferating cell nuclear
antigen PCNA (the processivity subunit of DNA polymerase
d
) and RFC
(the
r
eplication
f
actor
C
, responsible for loading PCNA onto DNA) are also
necessary when the nick is placed 3
0
to the mismatch.
63
The requirement of Exo1 when the nick is found 3
0
to the mismatch came
3
0
exonuclease.
64-66
It was initially proposed
as a surprise because Exo1 is a 5
0
!
5
0
exonuclease activity,
63
but no evidence was found.
The apparent inconsistency was resolved when Modrich and coworkers found
that human PMS2, one of the protomers that form the MutL
a
heterodimer, has
a latent endonuclease activity dependent on PCNA.
67
MutL
a
can cut DNA 5
0
or 3
0
to the mismatch, but it preferentially cleaves between the mismatch and a
preexisting nick. Therefore, the endonuclease activity of MutL
a
provides entry
sites for Exo1,
67
explaining why MutL
a
is strictly necessary to repair mis-
matches from a 3
0
nick, but dispensable when the nick is found 5
0
that Exo1 had cryptic 3
0
!
to the
mismatch.
63
C. The Multiple Faces of MutL
Eukaryotic MutL proteins coordinate not only DNA mismatch repair, but
also transcription-coupled nucleotide excision repair, DNA damage surveil-
lance, meiotic recombination, cell cycle checkpoint control, and apoptosis.
8
The physical interactions of eukaryotic MutL homologs with MutS homologs
PCNA, RFC, and Exo1 are well documented and have been shown to be
critical for mismatch repair.
28,68-76
Additionally, MutL
a
interacts with
MRE11 during the processing of double-strand breaks
77-79
and proteins
from the ATR-Chk1 pathway.
10,11,80
MutL
a
also interacts with BRCA1 and
the BRCA1-associated helicase BRIP1/BACH1,
60,81
which have critical roles in
homologous recombination, double-strand break, and intrastrand cross-link
repair.
82,83
In a similar manner, it has been proposed that by recruiting different
protein effectors,
E. coli
MutL determines the biological outcome of a lesion
recognized by MutS.
84,85
During mismatch repair, MutL interacts with MutS
and mismatched DNA to activate the endonuclease activity of MutH.
32,33,86
It interacts with helicase II (also known as uvrD) and activates its helicase
