Biology subjects

Malina, A.

Publications and source records attributed to Malina, A..

3 recordsLinked to original sources

bioRxiv2026

Saturated fatty acid chain length shapes B cell lymphoma metabolism and progression

B-cell lymphomas reprogram cellular metabolism to sustain their rapid growth and proliferation. Despite their close proximity to adipose tissue and the paradoxical association between obesity and improved lymphoma outcomes, how fatty-acid availability and dietary fat composition influence B-cell lymphoma remains poorly understood. Importantly, saturated fatty acids of different chain lengths have distinct routes of cellular uptake and metabolic fates and may therefore exert divergent effects on tumour growth. Here, we investigated how medium-chain and long-chain saturated fatty acids, their dietary availability, and their transfer from adipocytes shape B-cell lymphoma metabolism and progression. We found that B-cell lymphoma cells were dependent on fatty-acid uptake, activation, and utilization for proliferation. Additionally, we identified adipocytes as microenvironmental players that transfer fatty acids and suppress cell growth. Interestingly, in most B-cell lymphomas, exogenous palmitate limits lymphoma cell proliferation, while MCFA caprylic acid showed only mild effects. Using a syngeneic B-cell lymphoma orthotopic model, we found that an MCFA-rich diet increased lymphoma burden and accelerated lymph-node progression, whereas LCFA-rich and obesogenic diets restricted lymphoma dissemination. Dietary fatty-acid composition also altered T-cell exhaustion and profoundly remodelled the circulating lipidome, with LCFA-rich and obesogenic diets producing highly concordant lipidomic signatures distinct from MCFA feeding. Across B-cell lymphoma cell lines, low ACSL1 expression was associated with increased palmitate sensitivity, which we computationally modelled as a targetable vulnerability in B-cell lymphoma treatment. Taken together, our results show that lipid metabolism is a metabolic vulnerability that can be targeted through dietary intervention.

cancer biology↗

bioRxiv2022

C1orf112 is a novel regulator of interstrand crosslink that decreases FIGNL1-RAD51 interaction

Interstrand DNA crosslinks (ICLs) represent complex lesions that block essential biological processes, including DNA replication, recombination, and transcription. Several pathways have been involved in ICL repair, in particular nucleotide excision repair (NER), translesion DNA synthesis (TLS), Fanconi anemia (FA), and homologous recombination (HR). Still, the extent of factors involved in the resolution of ICL-induced DNA double-strand breaks (DSBs) remains poorly defined. Using CRISPR-based genome-wide screening, we identified the poorly characterized C1orf112 (also known as Apolo1) as a novel sensitizer to the clinically relevant ICL-inducing agent mafosfamide. Consistently, we noted that low expression of C1orf112 correlates with increased sensitivity to a series of ICL agents and PARP inhibitors in a panel of cell lines. We showed that lack of C1orf112 does not impact the initial recruitment and ubiquitylation of FANCD2 at the ICL site but rather impairs the resolution of RAD51 from ICL-induced DSBs, thereby compromising homology-directed DNA repair pathways. Our proximal mapping of C1orf112 protein neighbours coupled to structure-function analysis revealed that C1orf112, through its WCF motif, forms a complex with the N-terminal domain of the AAA+ ATPase FIGNL1 and regulates the interaction of FIGNL1 with RAD51. Our work establishes the C1orf112-FIGNL1 complex as an integral part of the HR-mediated response to ICLs by regulating the unloading of RAD51 during ICL repair.

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↗