Biology subjects

Sesay, F.

Publications and source records attributed to Sesay, F..

3 recordsLinked to original sources

bioRxiv2024

Dyrk1a is required for craniofacial development in Xenopus laevis.

Loss of function mutations in the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene are associated with craniofacial malformations in humans. Here we characterized the effects of deficient DYRK1A in craniofacial development using a developmental model, Xenopus laevis. Dyrk1a mRNA and protein was expressed throughout the developing head and was enriched in the branchial arches which contribute to the face and jaw. Consistently, reduced Dyrk1a function, using dyrk1a morpholinos and pharmacological inhibitors, resulted in orofacial malformations including hypotelorism, altered mouth shape, slanted eyes, and narrower face accompanied by smaller jaw cartilage and muscle. Inhibition of Dyrk1a function resulted in misexpression of key craniofacial regulators including transcription factors and members of the retinoic acid signaling pathway. Two such regulators, sox9 and pax3 are required for neural crest development and their decreased expression corresponds with smaller neural crest domains within the branchial arches. Finally, we determined that the smaller size of the faces, jaw elements and neural crest domains in embryos deficient in Dyrk1a could be explained by increased cell death and decreased proliferation. This study is the first to provide insight into why craniofacial birth defects might arise in humans with DYRK1A mutations.

developmental biology↗

bioRxiv2022

Inhibition of LATS Kinases in Ovarian Cancer Activates Cyclin D1/CDK4 and Decreases DYRK1A Activity

The controlled division of cells requires a coordination of multiple cellular pathways. Hippo pathway controls the organ size and restricts cell proliferation in response to the signals from cell surface receptors, and genetic alterations in the components of this pathway are common in cancer. LATS1 and LATS2 are homologous protein kinases that relay the signals from the environment to the Hippo effector YAP by direct phosphorylation that promotes its degradation. The genes encoding these kinases undergo frequent genetic losses in human cancers, with particularly high rates in high grade serous ovarian carcinoma (HGSOC), a highly lethal cancer with poorly understood mechanisms of pathogenesis and progression. We hypothesized that loss of LATS kinases could be a driver in this cancer and investigated signaling pathways downstream of LATS that could influence the ovarian cancer tumorigenic phenotypes. Depletion of both LATS1 and LATS2 was required to increase cell proliferation and disrupt the assembly of the cell-cycle regulatory DREAM complex. LATS-depleted human ovarian cancer cells formed bigger tumors in the immunocompromised mice, consistent with their tumor suppressor role. DREAM assembly depends on the activity of DYRK1A protein kinase, which was decreased in the LATS1/2-depleted cells. Furthermore, loss of LATS kinases increased the inhibitory phosphorylation of the retinoblastoma (Rb) family proteins, further promoting the DREAM disassembly that was rescued by CDK4 inhibitor palbociclib. Our study describes a crosstalk between the Hippo pathway and the cell cycle regulatory machinery converging on cyclin D1, a major regulator of the Rb tumor suppressor family, and highlights cellular pathways that could contribute to ovarian cancer pathogenesis and progression.

cancer biology↗

bioRxiv2018

DYRK1A regulates the recruitment of 53BP1 to the sites of DNA damage in part through interaction with RNF169

Human DYRK1A gene encoding Dual-specificity tyrosine (Y)- Regulated Kinase 1A (DYRK1A) is a dosage-dependent gene whereby either trisomy or haploinsufficiency result in developmental abnormalities. However, the function and regulation of this important protein kinase are not fully understood. Here we report proteomic analysis of DYRK1A in human cells that revealed a novel role of DYRK1A in the DNA double-strand break (DSB) repair signaling. This novel function of DYRK1A is mediated in part by its interaction with ubiquitin-binding protein RNF169 that regulates the choice between homologous recombination (HR) and non-homologous end joining (NHEJ) DSB repair. Accumulation of RNF169 at the DSB sites promotes homologous recombination (HR) by limiting the recruitment of the scaffold protein 53BP1 that promotes NHEJ by protecting the DNA ends from resection. Inducible overexpression of active, but not the kinase inactive, DYRK1A in U-2 OS cells inhibited accumulation of 53BP1 at the DSB sites in RNF169-dependent manner. Mutation of DYRK1A phosphorylation sites in RNF169 or pharmacological inhibition of DYRK1A using harmine decreased the ability of RNF169 to displace 53BP1 from radiation-induced DSB sites. In order to further investigate the role of DYRK1A in regulation of DNA repair, we used CRISPR-Cas9 mediated knockout of DYRK1A in human and mouse cells. Interestingly, knockout of DYRK1A also caused a defect in 53BP1 DSB recruitment that was independent of RNF169, suggesting that dosage of DYRK1A can influence the DNA repair processes through several mechanisms. U-2 OS cells devoid of DYRK1A displayed an increased DNA repair and HR efficiency, and showed a decreased sensitivity to the PARP inhibitor olaparib when compared to control cells. Given evidence of its altered expression in human cancers, DYRK1A levels could represent a significant determinant of the DNA damaging therapy response.

molecular biology↗