Biology subjects

Bayir, H.

Publications and source records attributed to Bayir, H..

4 recordsLinked to original sources

bioRxiv2026

Hydroperoxy-lipids Are Essential Yet Insufficient For Execution Of Ferroptosis

Cells with irreparable redox disbalance in membranes trigger a program of regulated death - ferroptosis. 15-lipoxygenase (LOX)-catalyzed accumulation of hydroperoxy-phosphatidyl-ethanolamines (HOO-PEs) has been associated with the execution of ferroptosis; yet, experimental proof of their sufficiency is lacking. Using the Fe-independent hydrophobic radical initiator, 2,2'-azobis(2,4-dimethyl)-valeronitrile (AMVN), we demonstrate that the accumulation of hydroperoxy-phospholipids (HOO-PLs) is necessary, but insufficient for driving ferroptosis. We further show that Fe-catalyzed decomposition of HOO-PLs into radical intermediates and oxidatively truncated (OxTr) electrophilic species, as well as the formation of protein adducts with OxTr electrophilic species are required for the completion of the ferroptotic program. Consequently, three types of agents - inhibitors of LOXs and other enzymatic generators of HOO-PLs, radical scavengers, and small-molecule nucleophiles - acting at different stages of lipid peroxidation during the ferroptotic program represent effective and specific ferroptosis regulators and potential therapeutic remedies.

biochemistry↗

bioRxiv2024

Targeting LxCxE cleft pocket of retinoblastoma protein in M2 macrophages inhibits ovarian cancer progression

AbstractOvarian cancer remains a major health threat with limited treatment options available. It is characterized by immunosuppressive tumor microenvironment (TME) maintained by tumor- associated macrophages (TAMs) hindering anti-tumor responses and immunotherapy efficacy. Here we show that targeting retinoblastoma protein (Rb) by disruption of its LxCxE cleft pocket, causes cell death in TAMs by induction of ER stress, p53 and mitochondria-related cell death pathways. A reduction of pro-tumor Rbhigh M2-type macrophages from TME in vivo enhanced T cell infiltration and inhibited cancer progression. We demonstrate an increased Rb expression in TAMs in women with ovarian cancer is associated with poorer prognosis. Ex vivo, we show analogous cell death induction by therapeutic Rb targeting in TAMs in post-surgery ascites from ovarian cancer patients. Overall, our data elucidates therapeutic targeting of the Rb LxCxE cleft pocket as a novel promising approach for ovarian cancer treatment through depletion of TAMs and re-shaping TME immune landscape. Statement of significanceCurrently, targeting immunosuppressive myeloid cells in ovarian cancer microenvironment is the first priority need to enable successful immunotherapy, but no effective solutions are clinically available. We show that targeting LxCxE cleft pocket of Retinoblastoma protein unexpectedly induces preferential cell death in M2 tumor-associated macrophages. Depletion of immunosuppressive M2 tumor-associated macrophages reshapes tumor microenvironment, enhances anti-tumor T cell responses, and inhibits ovarian cancer. Thus, we identify a novel paradoxical function of Retinoblastoma protein in regulating macrophage viability as well as a promising target to enhance immunotherapy efficacy in ovarian cancer.

immunology↗

bioRxiv2021

Persistent DNA damage rewires lipid metabolism and promotes histone hyperacetylation via MYS-1/Tip60.

Nuclear DNA damage is intricately linked to cellular metabolism. However, the underlying mechanisms and full range of metabolic alterations that occur in response to persistent DNA damage are not well understood. Here, we use a DNA repair-deficient model of ERCC1-XPF in Caenorhabditis elegans (C. elegans), that accumulates physiologically relevant, endogenous DNA damage, to gain molecular insights on how persistent genotoxic stress drives biological aging. Using an integrated multi-omic approach, we discover that persistent genotoxic stress rewires lipid metabolism. In particular, nuclear DNA damage promotes mitochondrial {beta}-oxidation and leads to a global loss of fat depots. This metabolic shift to {beta}-oxidation generates acetyl-CoA and drives histone hyperacetylation. Concomitantly, we observe an associated change in gene expression of immune-effector and cytochrome (CYP) genes. We identify MYS-1, the ortholog of mammalian histone acetyltransferase TIP60, as a critical regulator of this metabolic-epigenetic axis. Moreover, we show that in response to persistent DNA damage, polyunsaturated fatty acids (PUFAs), especially arachidonic acid (AA) and AA-related lipid mediators are elevated. This elevation of PUFA species requires mys-1/Tip60. Together, these findings reveal that persistent nuclear DNA damage alters the metabolic-epigenetic axis to drive an immune-like response that can promote age-associated decline.

cell biology↗

bioRxiv2017

Quantitative Assessment Of Cell Fate Decision Between Autophagy And Apoptosis

Autophagy and apoptosis regulate cell survival and death, and are implicated in the pathogenesis of many diseases. The same type of stress signals can induce either process, but it is unclear how cells assess cellular damage and make a life or death decision by activating autophagy or apoptosis. A computational model of coupled apoptosis and autophagy is built here to study the systems-level dynamics of the underlying signaling network. The model explains the differential dynamics of autophagy and apoptosis in response to various experimental stress signals. Autophagic response dominates at low-to-moderate stress; whereas the response shifts from autophagy (graded activation) to apoptosis (switch-like activation) with increasing intensity of stress. The model reveals that this dynamic cell fate decision is conferred by a core regulatory network involving cytoplasmic Ca2+ as a rheostat that fine-tunes autophagic and apoptotic responses. A G-protein signaling-mediated feedback loop maintains cytoplasmic Ca2+ level, which in turn governs autophagic response through an AMP-activated protein kinase (AMPK)-mediated feedforward loop. The model identified Ca2+/calmodulin-dependent kinase kinase {beta} (CaMKK{beta}) as a determinant of the opposite roles of cytoplasmic Ca2+ in autophagy regulation. The results also demonstrated that the model could contribute to the development of pharmacological strategies modulate cell fate decisions.

systems biology↗