Role of Brca1 and Brca2 in DNA Repair
DNA damage-dependent activation of the breast and ovarian cancer susceptibility
protein 1 (Brca1) occurs via activation of ataxia
telangiectasia mutated serine-protein kinase
(ATM)  or ataxia
telangiectasia and Rad3 related protein kinase
(ATR) . These kinases
phosphorylate Brca1 directly or indirectly
(via cell cycle checkpoint kinase 2
(Chk2) ). Phosphorylated
by ATM and ATR histones
(H2AX) are co-localized together with some proteins to form
nuclear foci at DNA damage sites. The loci can include the tumor protein 53-binding
protein, 1 (53BP1) and the
nuclear factor with BRCT domians protein 1
(NFBD1), which take part in activation of
Chk2 , MRN
complex (consisting from double-strand break repair protein
(Mre11), Rad50 homolog (S.
cerevisiae) (Rad50) and Nijmegen breakage syndrome 1 protein
(Nibrin)) is a part of these foci, as well.
One suggested response of Brca1 to DNA damage consists of
monoubiquitination of H2AX, followed by remodeling the
chromatin in such a way that damaged DNA becomes assessable to the DNA repair machinery
. E3 ubiquitin ligase activity of Brca1
considerably amplifies, if Brca1 forms a
complex with a Brca1 associated RING domain protein 1
Brca1 plays a central role in DNA repair by facilitating
cellular response to DNA repair. There are numerous DNA repair pathways directed to the
specific types of damage, and a given type of damage can be targeted by several pathways.
Major DNA repair pathways are mismatch repair (MMR), nucleotide excision repair (NER),
base excision repair (BER), homologous recombinational repair (HRR), and non-homologous
end joining (NHEJ) .
Brca1 participates in all these pathways.
Participation Brca1 in NER is mediated by transcription
factors p53 and SP1. These TFs
activate transcription of damage-specific DNA binding protein 2
(DDB2) and xeroderma pigmentosum group C protein
(XPC). In addition, activated by
Brca1, p53 participates in BER by exciting
transcription of proliferating cell nuclear antigen (PCNA)
and stimulating activity of the endonuclease III-like 1 enzyme
Moreover, Brca1 seems to be involved in DNA repair
processes such as transcription-coupled repair (TCR) via activation of RNA polymerase II
transcription machinery , .
Both Brca1 and Brca2 are
implicated in HRR via DNA repair protein, S.cerevisiae homolog
RAD51. RAD51 is a key component
of the mechanism in which DNA damage is repaired by homologous recombination . Moreover, Brca1 may activate Brca1 interacting
protein C-terminal helicase 1 (BRIP1) .
BRIP1 is able to catalytically release the third strand of
the homologous recombination intermediate D-loop structure irrespective of DNA tail
It is shown that Fanconi anemia complementation group D2 protein, isoform 1
(FANCD2) (in a complex with
RAD51 and/or Brcas)
participates in HRR . At the same time,
FANCD2 should be ubiquitinated (by a complex of Fanconi
(FANC complex), for example) . Moreover, Fanconi anemia proteins/Brca1 pathway
participates in DNA interstrand cross-link (ICL) repair .
Role of Brca1 in NHEJ
consists of regulation of the MRN
complex. Phosphorylated by
Chk2, Brca1 inhibits
Mre11. It depresses NHEJ pathway and stimulates
HRR RAD51-dependent pathway . In
addition, Brca1 may stimulate HRR and NHEJ via activation
of Rad50 , .
Brca1 and BARD1 are
downstream effectors of the adenosine nucleotide-activated DNA mismatch repair protein
signaling complex (MSH2,
MLH1), and suggest a global role for Brca1 in
MMR . It is shown, that p53 take part of MMR
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