The regulatory functions of lncRNAs inBRCA۱/۲ expression in breast cancer

Breast cancer is one of the most common malignancies and lethalcancer in women. about ۷۰% of breast cancer cases are sporadicand other cases are known as hereditary. Pathogenic variantsin the high-penetrance genes BRCA۱ and BRCA۲ accountfor approximately ۲۰% of heritable breast cancer risk. They areboth classic tumor suppressor genes, which are involved in themaintenance of genomic stability by facilitating DNA repair.BRCA۲ contains eight BRCT repeats, each of which can bindand recruit RAD۵۱ to sites of DNA damage.RNA-based therapeutics against cancer have gradually changedfrom concept to reality. Among these therapeutics, non-codingRNA (ncRNA), which refers to a class of RNA that does not encodea protein, exerts clinical therapeutic effects against tumorsby inhibiting the transcription of mRNA and binding to proteinto block its function. Long non-coding RNAs (nt>۲۰۰) are involvedin diverse biological processes such as cell proliferation,differentiation, chromosome remodeling, epigenetic modulation,and transcriptional and posttranscriptional modifications.BRCA۱ and BRCA۲ are essential for the repair of dsDNAbreaks (DSBs) by homologous recombination. They undertakedistinct functions during this process that are well studied, andtherefore only briefly recounted here. Notably, BRCA۱ andBRCA۲ form a tri-molecular complex with a partner protein,PALB۲, that assists in their localization and function at sitesof DNA damage. Put simply, BRCA۱ acts first to assemblemacromolecular complexes that signal the presence of DNAdamage and subsequently helps to initiate the repair of DSBsby recruiting proteins that process broken ends. By contrast,BRCA۲ participates directly in controlling the activity and assemblyof the key recombination enzyme, RAD۵۱, on ss- anddsDNA substrates to execute DNA repair by HR.PCAT۱ is the most differentially expressed lncRNA in prostatecancer. Shortly afterward it was discovered that this lncRNAregulates the important tumor suppressor BRCA۲. Specifically,it was shown that PCAT۱ reduces BRCA۲ mRNA stability.Findings appear to support that the first ۲۵۰ nt of PCAT۱ plays an important role due to the high frequency of interaction withtargets and no significant binding with RBPs.Prior studies suggest that DNA breakage triggers the synthesisby RNAPII of damage-induced long non-coding RNAs (dilncRNAs)or shorter transcripts from broken DNA ends, whichpromote the sensing, signaling, and repair of these lesions. Recentevidence suggests that the dilncRNAs anneal with resectedends at DSBs to form RNA-DNA hybrids that are recognizedby BRCA۱, in turn, assist in the recruitment of BRCA۲ andRAD۵۱. Interestingly, BRCA۲ engages RNase H۲ and recruitsthis enzyme to DSBs, where it regulates the turnover of RNADNAhybrids at the damage sites. Thus, these studies collectivelysuggest that BRCA۱ and BRCA۲ may promote the repairof DSBs by HR through the processing of DNA-RNA hybridsformed at the lesions.In this review, we focused on summarizing the known effectsof lncRNAs in regulating the expression of BRCA۱/۲ genes,which play an important role in the biogenesis and progressionof breast cancer.

کلیدواژه ها:

Breast Neoplasms ، RNA ، Long Noncoding ، Genes ، BRCA۱ ، Genes ، BRCA۲ ، Neoplasm Metastasis ، HomologousRecombination