Biology Reference
In-Depth Information
The CTRB region that interacts with RAD51 is seen only in vertebrates and
this region binds RAD51 filaments, but not free RAD51, likely to stabilize the
NPF.
187,188
CDK phosphorylation of BRCA2(S3291) appears to inhibit its inter-
action with the RAD51 filament, leading to its disassembly.
188,200
As might be
predicted, during the S phase when RR is highly active, there is very low BRCA2
(S3291) phosphorylation that gradually increases with the approach of the M
phase.
200
These results suggest that the CTRB region functions as a cell cycle
regulator of RR. In addition, the C terminus of BRCA2 is essential for the
nuclear transport of RAD51 from the cytoplasm as RAD51 lacks a nuclear
localization signal (NLS; Refs.
201,202
). Thus, in human pancreatic cancer cell
line CAPAN-1 that expresses a truncated version of BRCA2 (BRCA26174delT;
Ref.
203
), BRCA2 transportation into the nucleus is compromised and the levels
of nuclear RAD51 are greatly diminished.
201
Finally, it has been recently shown
that the CTRB region of BRCA2 is essential for protection of stalled replication
forks against the MRE11 nuclease by stabilizing the RAD51 NPF.
204,205
BRCA2 has also been shown to interact with DMC1 through a mammalian-
specific 26 amino acid interaction motif containing BRCA2 residues
2386-2411.
206
This motif contains three critical amino acids, BRCA2 F2406,
P2408, and P2409 (PhePP motif), that are essential for DMC1 interaction.
206
The N terminus of BRCA2 has also been shown to interact with RPA in a DNA-
independent manner by co-immunoprecipitation
207
and the cancer-predisposing
mutation BRCA2(Y42C) compromises this interaction.
207
PALB2 (partner and localizer of BRCA2), also known as FANCN due to its
involvement in FA,
208
interacts with the N terminus of BRCA2 and was shown
to be essential for stable nuclear localization, recombination, and checkpoint
functions of the latter.
209
The BRCA2(Y42C) also disrupts the interaction with
PALB2.
209
In addition, PALB2 has been shown to stimulate RAD51-catalyzed
D-loop formation by physically interacting with RAD51 and displays a coop-
erative effect in the presence of RAD51AP1, another stimulator of RAD51
recombinase activity.
210,211
DSS1 (the
deleted in split hand/split foot
gene) is a small acidic protein first
shown to interact with BRCA2 by yeast and mammalian two-hybrid assays.
212
Disruption of DSS1 leads to compromised RAD51 foci formation and
DSB repair in both fungal and mammalian species.
213,214
DSS1 binds to the
DNA-binding region of BRCA2,
215
and in
U. maydis
, Dss1 prevents dimeriza-
tion of Brh2, allowing the formation of a monomeric functional protein.
216
These seemingly contradictory phenotypes will require some resolution in the
coming years.
Other than the role of BRCA2 in DSB repair, it is also suggested to be
involved in post-replication repair of ssDNA gaps by a template switch mech-
anism due to damage in the original template.
117
In fact, studies with Brh2 have
confirmed the template switch mechanism
in vitro
.
217
