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DNA damage Role of Brca1 and Brca2 in DNA repair

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DNA damage Role of Brca1 and Brca2 in DNA repair

Role of Brca1 and Brca2 in DNA Repair

DNA damage-dependent activation of the breast and ovarian cancer susceptibilityprotein 1 ( Brca1 ) occurs via activation of ataxia telangiectasia mutatedserine-protein kinase ( ATM ) [1] or ataxia telangiectasia and Rad3related protein kinase ( ATR ) [2]. These kinases phosphorylateBrca1 directly or indirectly (via c ell cycle checkpoint kinase 2 ( Chk2 )[3]). 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 ) andthe nuclear factor with BRCT domians protein 1 ( NFBD1 ), which take partin activation of Chk2 [4], MRN complex (consisting fromdouble-strand break repair protein ( Mre11 ), Rad50 homolog (S. cerevisiae) (Rad50 ) and Nijmegen breakage syndrome 1 protein ( Nibrin )) is a part ofthese foci, as well.

One suggested response of Brca1 to DNA damage consists of monoubiquitination ofH2AX, followed by remodeling the chromatin in such a way that damaged DNA becomesassessable to the DNA repair machinery [5]. E3 ubiquitin ligase activity ofBrca1 considerably amplifies, if Brca1 forms a complex with a Brca1associated RING domain protein 1 ( BARD1 ) [6].

Brca1 plays a central role in DNA repair by facilitating cellular response toDNA repair. There are numerous DNA repair pathways directed to the specific types ofdamage, and a given type of damage can be targeted by several pathways. Major DNA repairpathways are mismatch repair (MMR), nucleotide excision repair (NER), base excisionrepair (BER), homologous recombinational repair (HRR), and non-homologous end joining(NHEJ) [7].

Brca1 participates in all these pathways.

Participation Brca1 in NER is mediated by transcription factors p53 andSP1. 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 ofproliferating cell nuclear antigen ( PCNA ) and stimulating activity of theendonuclease III-like 1 enzyme ( Nth1 ).

Moreover, Brca1 seems to be involved in DNA repair processes such astranscription-coupled repair (TCR) via activation of RNA polymerase II transcriptionmachinery [8], [9].

Both Brca1 and Brca2 are implicated in HRR via DNA repair protein,S.cerevisiae homolog RAD51. RAD51 is a key component of the mechanism inwhich DNA damage is repaired by homologous recombination [10]. Moreover,Brca1 may activate Brca1 interacting protein C-terminal helicase 1 ( BRIP1) [11]. BRIP1 is able to catalytically release the third strand of thehomologous recombination intermediate D-loop structure irrespective of DNA tail status[12].

It is shown that Fanconi anemia complementation group D2 protein, isoform 1 (FANCD2 ) (in a complex with RAD51 and/or Brca s) participates in HRR[13]. At the same time, FANCD2 should be ubiquitinated (by a complexof Fanconi anemia proteins ( FANC complex ), for example) [14].Moreover, Fanconi anemia proteins/ Brca1 pathway participates in DNA interstrandcross-link (ICL) repair [15].

Role of Brca1 in NHEJ consists of regulation of the MRN complex.Phosphorylated by Chk2, Brca1 inhibits Mre11. It depresses NHEJpathway and stimulates HRR RAD51 -dependent pathway [3]. In addition,Brca1 may stimulate HRR and NHEJ via activation of Rad50 [16], [17].

Brca1 and BARD1 are downstream effectors of the adenosinenucleotide-activated DNA mismatch repair protein signaling complex ( MSH2,MSH3, MSH6, MLH1 ), and suggest a global role for Brca1 inMMR [18]. It is shown, that p53 take part of MMR [19].