Biology Reference
In-Depth Information
The Role of ATM and ATR in Other DNA
Repair Pathways
ATM and ATR not only regulate HRR but also other
DNA repair pathways. For example, ATR is known to
interact with and phosphorylate proteins in the nucleo-
tide excision repair (NER), mismatch repair (MMR),
base excision repair (BER), and translesion DNA
synthesis (TLS) pathways.
1,55
Furthermore, recent
studies suggested that ATR is a key regulator of the
repair of interstrand DNA crosslink (ICL) by the Fanconi
anemia (FA) pathway. ATM also has roles in DNA repair
beyond HR. A recent mouse study revealed that ATM is
critical for NHEJ in the absence of XLF.
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Another study
suggested that ATM, H2AX, and MDC1 prevent CtIP-
mediated resection of DNA ends during G1 of the cell
cycle, a period when HR does not operate.
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Interest-
ingly, while ATM and
-H2AX may play a positive
role in HR by facilitating the recruitment of BRCA1,
they also promote the recruitment of 53BP1, a protein
that antagonizes the function of BRCA1 and facilitates
NHEJ.
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It has been suggested that ATM promotes
NHEJ in G1 but HR in G2.
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Therefore, the functions
of ATM and ATR in DNA repair are intricately regulated
by the exact structure of DNA lesion, the chromatin
context, the cell-cycle status, and the interplay among
different DNA repair pathways.
g
HRR at Stalled or Collapsed DNA Replication
Forks
HRR at Replication Forks
HRR not only occurs at DSBs but also at replication
forks encountering problems. The progression of repli-
cation forks along chromosomal DNA could be impeded
by many different DNA structures and cellular stresses,
such as reduction of dNTP levels, bulky DNA adducts,
intra-strand crosslinks or ICL, SSB or DSB, repetitive
DNA sequences, compacted chromatin structures, and
certain protein
e
DNA complexes (reviewed in
91,92
).
Depending on the nature of replication blockage,
different DNA repair pathways are invoked to promote
the recovery of stalled forks. Genetic evidence strongly
suggests that the HRR pathway is critical for the stabili-
zation and/or recovery of stalled replication forks.
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e
95
HRR proteins such RAD51, BRCA1, and BRCA2 are
important for the maintenance of replication forks in
the presence of replication stress.
How exactly HRR occurs at stalled replication forks is
still poorly understood. When DNA polymerases on the
leading or lagging strand are blocked by DNA lesions,
the 3
0
ends of nascent DNA strands could anneal with
the complementary sequences in the opposite arm of
replication forks. This process, which could generate D
loops or crossovers like those formed at DSBs, is termed
FIGURE 7.3
Chromatin-mediated recruitment of repair proteins.
An ATM- and MDC1-mediated positive feedback loop promotes
H2AX phosphorylation across the chromatin flanking DSBs. MDC1
brings in RNF8 to ubiquitinate H2A and H2AX. The polyubiquitin
chains generated by RNF8 recruit the BRCA1-A complex via RAP80.
RAD18 directly interacts with RAD51C, and is impor-
tant for the recruitment of RAD51C to DSBs.
The function of ATM in DSB repair is influenced by
the chromatin context in which DSBs reside. It has
been suggested that ATM is particularly important for
the repair of DSBs in the heterochromatic regions (about
15% of total DSBs).
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In response to IR, ATM phosphor-
ylates the heterochromatin-binding protein KAP-1.
85
In
contrast to BRCA1, phosphorylated KAP-1 is rapidly
released from chromatin around DSBs. The phosphory-
lation of KAP-1 is important for DNA damage-induced
chromatin relaxation.
85
Ablation of KAP-1 leads to
constitutive chromatin relaxation, and partially allevi-
ates the requirement of ATM for HRR.
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