Biology subjects

Samiei, A.

Publications and source records attributed to Samiei, A..

3 recordsLinked to original sources

bioRxiv2026

PRMT5 is Frequently Upregulated and a Potential Therapeutic Target in MTAP-deficient Malignant Peripheral Nerve Sheath Tumors

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive sarcomas with poor prognosis and a strong tendency for metastasis and relapse. Surgical removal remains the mainstay of treatment but is frequently ineffective or impractical. Currently, no effective targeted therapy exists for this type of malignancy. PRMT5 has recently emerged as a promising therapeutic target in various human cancers with MTAP loss, which results in cancer cell dependency on PRMT5 activity. The frequent loss of MTAP in MPNSTs suggests that PRMT5 inhibition is a promising therapeutic option and enables the stratification of cancer patients with few treatment options. We first examined human nerve sheath tumor samples and found that increased PRMT5 expression and activity correlated with MTAP loss in 86.8% (33/38) of MPNSTs and in atypical neurofibromatous neoplasm with uncertain biologic potential (ANNUBP) (5/5). When PRMT5 activity was inhibited genetically and chemically, the cell growth of MTAP-deficient MPNST cell lines was suppressed, but not that of MTAP-proficient MPNST cell lines. Moreover, in the PRMT5-inhibited MTAP-deficient MPNST cell lines, spontaneous DNA damage accumulation was observed following G2/M cell cycle arrest. The DNA replication stress marker RPA32 decreased, and CHK1 was activated early after PRMT5 knockdown, likely contributing to the accumulation of DNA damage. In addition, we combined PRMT5 inhibition with the DNA-damaging agents doxorubicin and gemcitabine, resulting in synergistic effects and increased cancer cell death in MTAP-deficient MPNST cell lines. Together, these findings identify PRMT5 as a compelling therapeutic target in MTAP-deficient MPNSTs. This PRMT5 inhibition strategy has strong translational potential for MPNSTs. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/710638v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@15abc35org.highwire.dtl.DTLVardef@1fa4ebborg.highwire.dtl.DTLVardef@470c51org.highwire.dtl.DTLVardef@79cc3f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

The eEF2 kinase coordinates the DNA damage response to cisplatin by supporting p53 activation

Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) is a stress-responsive hub that inhibits the translation elongation factor eEF2, and consequently mRNA translation elongation, in response to hypoxia and nutrient deprivation. EEF2K is also involved in the response to DNA damage but its role in response to DNA crosslinks, as induced by cisplatin, is not known. Here we found that eEF2K is critical to mediate the cellular response to cisplatin. We uncovered that eEF2K deficient cells are more resistant to cisplatin treatment. Mechanistically, eEF2K deficiency blunts the activation of the DNA damage response associated ATM and ATR pathways, in turn preventing p53 activation and therefore compromising induction of cisplatin-induced apoptosis. We also report that loss of eEF2K delays the resolution of DNA damage triggered by cisplatin, suggesting that eEF2K contributes to DNA damage repair in response to cisplatin. In support of this, our data shows that eEF2K promotes the expression of the DNA repair protein ERCC1, critical for the repair of cisplatin-caused DNA damage. Finally, using Caenorhabditis elegans as an in vivo model, we find that deletion of efk-1, the worm eEF2K ortholog, mitigates the induction of germ cell death in response to cisplatin. Together, our data highlight that eEF2K represents an evolutionary conserved mediator of the DNA damage response to cisplatin which promotes p53 activation to induce cell death, or alternatively facilitates DNA repair, depending on the extent of DNA damage.

molecular biology↗

bioRxiv2018

FAM35A co-operates with REV7 to coordinate DNA double-strand break repair pathway choice.

DNA double-strand breaks (DSBs) can be repaired by two major pathways: non-homologous end-joining (NHEJ) and homologous recombination (HR). DNA repair pathway choice is governed by the opposing activities of 53BP1, in complex with its effectors RIF1 and REV7, and BRCA1. However, it remains unknown how the 53BP1/RIF1/REV7 complex stimulates NHEJ and restricts HR to the S/G2 phases of the cell cycle. Using a mass spectrometry (MS)-based approach, we identify 11 high-confidence REV7 interactors and elucidate the role of a previously undescribed factor, FAM35A/SHDL2, as a novel effector of REV7 in the NHEJ pathway. FAM35A depletion impairs NHEJ-mediated DNA repair and compromises antibody diversification by class switch recombination (CSR) in B-cells. FAM35A accumulates at DSBs in a 53BP1-, RIF1- and REV7-dependent manner and antagonizes HR by limiting DNA end resection. In fact, FAM35A is part of a larger complex composed of REV7 and another previously uncharacterized protein, C20orf196/SHDL1, which promotes NHEJ and limits HR. Together, these results establish FAM35A as a novel effector of REV7 in controlling the decision-making process during DSB repair.

cancer biology↗