BRAP-2 promotes DNA damage induced germline apoptosis in C. elegans through the regulation of SKN-1 and AKT-1

Abstract

As part of the DNA damage response (DDR) network, the tumour suppressor Breast cancer susceptibility gene 1 (BRCA1) is activated to facilitate DNA repair, transcription and cell cycle control. BRC-1, the Caenorhabditis elegans ortholog of BRCA1, has conserved function in DNA double strand break repair, wherein a loss of brc-1 results in high levels of germline apoptosis. BRAP2/IMP was initially identified as a BRCA1 associated binding protein and previously we have shown that the C. elegans brap-2 deletion mutant experiences BRC-1 dependent larval arrest when exposed to low concentrations of paraquat. Since BRC-1 function in the germline is conserved, we wanted to determine the role of BRAP-2 in DNA damage induced germline apoptosis in C. elegans. We examined levels of germ cell death following DNA damage and found that brap-2(ok1492) mutants display reduced levels of germline apoptosis when compared to the wild type, and the loss of brap-2 significantly reduced germ cell death in brc-1 mutant animals. We also found increased mRNA levels of skn-1 following DNA damage in brap-2 mutants and that skn-1 RNAi knockdown in brap-2;brc-1 double mutants and a loss of pmk-1 mutation in brap-2 mutants increased apoptosis to wild type levels, indicating that brap-2 promotion of cell survival requires PMK-1 and SKN-1. Since mammalian BRAP2 has been shown to bind the AKT phosphatase PHLPP1/2, it suggests that BRAP2 could be involved in the Insulin/Insulin-like growth factor Signaling (IIS) pathway. We found that this interaction is conserved between the C. elegans homologs and that a loss of akt-1 in brap-2 mutants increased germline apoptosis. Thus in response to DNA damage, our findings suggest that BRAP-2 is required to attenuate the pro-cell survival signals of AKT-1 and PMK-1/SKN-1 to promote DNA damage induced germline apoptosis.

The rice bran peptide KF-8 extends the lifespan and improves the healthspan of Caenorhabditis elegans via skn-1 and daf-16

“…This journal is © The Royal Society of Chemistry 2022 expression, 37 and the PMK-1 and p38 MAPK pathways are involved in stress and aging. 38 The skn-1 transcription factor regulates the transcriptional level of gcs-1.…”

Trilobatin, a Component from Lithocarpus polystachyrus Rehd., Increases Longevity in C. elegans Through Activating SKN1/SIRT3/DAF16 Signaling Pathway

“…Emerging evidence suggests that SOD2 is the downstream of SIRT3, which is located in mitochondria and attenuated mitochondrial ROS (Katwal et al, 2018). In our previous study, a major upstream of SIRT3 that has been proved is NRF2, which is encoded as SKN1 gene on C. elegans (Gao et al, 2018;D'Amora et al, 2018). Our results demonstrated that TLB upregulated the protein expressions of SKN1 and SIRT3, thereby exerting its anti-oxidantive effect; whereas, the anti-oxidantive effect of TLB were almost eliminated in SKN1 and SIRT3 mutant C. elegans, which indicated that NRF2/SIRT3 signaling pathway was involved in the anti-aging effects of TLB in C. elegans.…”

BRAP2 inhibits the Ras/Raf/MEK and PI3K/Akt pathways in leukemia cells, thereby inducing apoptosis and inhibiting cell growth

“…A recent report showed that BRAP2 knockdown led to an increase in the phosphorylation levels of Akt and mTOR in glioma cells (38), and our result was consistent with that report. BRAP2 binds PHLPP1 (27,39) which is involved in Akt activation (28,29), and it has been suggested that BRAP2 suppresses Akt through PHLPP1 to promote apoptosis induction (39). Therefore, we thought that the phosphorylation level of Akt may have been increased because BRAP2 deletion could not suppress Akt through PHLPP1.…”