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 susceptibility protein 1 (Brca1) occurs via activation of ataxia telangiectasia mutated serine-protein kinase (ATM) [1] or ataxia telangiectasia and Rad3 related protein kinase (ATR) [2]. These kinases phosphorylate Brca1 directly or indirectly (via cell 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) and the nuclear factor with BRCT domians protein 1 (NFBD1), which take part in activation of Chk2 [4], 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 [5]. E3 ubiquitin ligase activity of Brca1 considerably amplifies, if Brca1 forms a complex with a Brca1 associated RING domain protein 1 (BARD1) [6].

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) [7].

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 (Nth1).

Moreover, Brca1 seems to be involved in DNA repair processes such as transcription-coupled repair (TCR) via activation of RNA polymerase II transcription machinery [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 in which 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 the homologous 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 Brcas) participates in HRR [13]. At the same time, FANCD2 should be ubiquitinated (by a complex of Fanconi anemia proteins (FANC complex), for example) [14]. Moreover, Fanconi anemia proteins/Brca1 pathway participates in DNA interstrand cross-link (ICL) repair [15].

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 [3]. In addition, Brca1 may stimulate HRR and NHEJ via activation of Rad50 [16], [17].

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

References:

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