Abstract
Breast cancer has replaced cervical cancer as being the most common and having the highest mortality among women in India. ANKLE gene is conserved among organisms during evolutionary succession and is a member of LEM family proteins in lower metazoans and is involved in critical functions in the nuclear architecture, gene expression and cell signaling. ANKLE1 is the human orthologous of LEM-3 and is involved in DNA damage response and DNA repair. Whole Exome Sequencing (WES) of paired breast cancer samples was performed and ANKLE1 was found to be a new possible hotspot for predisposition of breast cancer. The mass array genotyping for breast cancer variant rs2363956 further confirmed the ANKLE1 association with the studied population of breast cancer. To elucidate the role of ANKLE1 in DNA damage, it was knocked down in MCF-7 breast cancer cell line and the expression of γH2AX was assessed. ANKLE1 knockdown cells displayed elevated levels of γ-H2AX foci in response to the cisplatin induced replication stress. The localization pattern of ANKLE1 further emphasized the role of ANKLE1 in DNA repair process. We observed that ANKLE1 is required for maintaining genomic stability and plays a role in DNA damage and repair process. These findings provided a molecular basis for the suspected role of ANKLE1 in human breast cancer and suggested an important role of this gene in controlling breast cancer development among women in India.
Highlights
Cancer development is a multistage process involving several genetic alterations (Takashi et al, 1992)
We have reported the role of ANKLE1 in DNA repair process, it’s mitigating action on the DNA damage in MCF-7 cell lines and an elevated DNA damage with knockdown of ANKLE1 gene
In this study we have demonstrated that ANKLE1, a potential DNA repair candidate, repairs the DNA damage caused by the treatment of MCF-7 cells with cisplatin
Summary
Cancer development is a multistage process involving several genetic alterations (Takashi et al, 1992). The development of cancers involves lacunae in the DNA repair pathways. The most frequent mutations in breast cancer are associated with DNA repair mechanisms in the cell (Ciriello et al, 2013). Several genes BRCA1, BRCA2, PALB2, CHEK2, PTEN, RAD51, RAD52, XRCC1, XRCC2 have been characterized for their involvement in hereditary or sporadic breast cancers (Walsh et al, 2006; Majidinia and Yousefi, 2017). The common alleles discovered by GWAS in the general population confer a higher risk in BRCA1 and BRCA2 mutations (Simon et al, 2007). Inherited mutations in these genes confer a lifetime risk of breast cancer (Paula et al, 2009). BRCA family of genes plays critical role in DNA Damage response and Repair
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