Biology subjects

Bellani, M.

Publications and source records attributed to Bellani, M..

3 recordsLinked to original sources

bioRxiv2025

The TONSL-MMS22L complex and FANCM form an interdependent complex on chromatin to counter replication stress

FANCM is branchpoint DNA translocase essential for cellular response to replication stress. Here, we show that replication stress stimulates FANCM and the TONSL-MMS22L heterodimer bound to histones H3-H4 to form an interdependent complex on chromatin. TONSL-MMS22L recruits FANCM and Fanconi anemia (FA) core complex to stalled and collapsed forks, maintains FANCM on replication-stressed chromatin, promotes FANCD2 monoubiquitination, facilitates both repair and replication traverse of DNA interstrand crosslinks (ICLs), and suppresses sister chromatid exchanges, through its interactions with FANCM and H3-H4. Reciprocally, both DNA translocase activity and phosphorylation of FANCM facilitate recruitment of TONSL-MMS22L and RAD51 to perturbed forks. Moreover, TONSL-MMS22L and FANCM function together to promote activation of the FA pathway, ICL repair, homologous recombination and replication traverse. Cancer patients with tumors with wildtype FANCM and low expression of TONSL-MMS22L have a more favorable prognosis than those with high expression. Thus, FANCM-TONSL-MMS22L acts coordinately as a complex on chromatin that resolves replication stress, and this complex may present a therapeutic target for wildtype FANCM-linked cancer.

cell biology↗

bioRxiv2024

A generalizable normative deep autoencoder for brain morphological anomaly detection: application to the multi-site StratiBip dataset on bipolar disorder in an external validation framework.

The heterogeneity of psychiatric disorders makes researching disorder-specific neurobiological markers an ill-posed problem. Here, we face the need for disease stratification models by presenting a generalizable multivariate normative modelling framework for characterizing brain morphology, applied to bipolar disorder (BD). We employed deep autoencoders in an anomaly detection framework, combined with a confounder removal step integrating training and external validation. The model was trained with healthy control (HC) data from the human connectome project and applied to multi-site external data of HC and BD individuals. We found that brain deviating scores were greater, more heterogeneous, and with increased extreme values in the BD group, with volumes prominently from the basal ganglia, hippocampus and adjacent regions emerging as significantly deviating. Similarly, individual brain deviating maps based on modified z scores expressed higher abnormalities occurrences, but their overall spatial overlap was lower compared to HCs. Our generalizable framework enabled the identification of subject- and group-level brain normative-deviating patterns, a step forward towards the development of more effective and personalized clinical decision support systems and patient stratification in psychiatry.

neuroscience↗

bioRxiv2024

A bifunctional antibody conjugate marks the location of DNA binding proteins on deproteinized DNA fibers.

Immunofluorescent foci of DNA Damage Response (DDR) proteins serve as surrogates for DNA damage and are frequently interpreted as denoting specific lesions. For example, Double Strand Breaks (DSBs) are potent inducers of the DDR, whose best-known factor is the phosphorylated histone variant H2AX ({gamma}-H2AX). The association with DSBs is so well established that the reverse interpretation that {gamma}-H2AX invariably implies DSBs is routine. However, this conclusion is inferential and has been challenged. The resolution of this question has been hampered by the lack of methods for distinguishing the location of DDR proteins relative to DSBs caused by sequence indifferent agents. Here, we describe an approach for marking the location of DDR factors in relation to DSBs on DNA fibers. We synthesized a two-arm "Y" conjugate containing biotin and trimethylpsoralen (TMP) coupled to a secondary antibody. After exposure to a DNA breaker, permeabilized mammalian cells were incubated with a primary antibody against the DDR factor followed by binding of the secondary antibody in the conjugate to the primary antibody. Exposure to longwave UV light covalently linked the psoralen to the DNA. DNA fibers were spread, and the immunofluorescence of the biotin tag denoted the location of the target protein. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/609705v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@15eaf5corg.highwire.dtl.DTLVardef@14ade70org.highwire.dtl.DTLVardef@51c83forg.highwire.dtl.DTLVardef@131cb58_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG

biochemistry↗