Biology subjects

Canela, A.

Publications and source records attributed to Canela, A..

3 recordsLinked to original sources

bioRxiv2026

Human FACT complex coordinates cohesin and transcription on chromatin

The spatial organisation of eukaryotic genomes is critical for coordinating DNA-dependent processes such as transcription and replication. Cohesin contributes to this organisation by extruding chromatin loops; however, how cohesin achieves processive translocation along nucleosome-dense chromatin in vivo remains poorly understood. Here, we identify the histone chaperone FACT as a regulator of cohesin dynamics in human cells. We show that the FACT subunit SUPT16H colocalises and interacts with cohesin on chromatin. Depletion of FACT impairs cohesin translocation from its loading sites, leading to reduced chromatin looping and decreased boundary strength of topologically associating domains (TADs), as revealed by Hi-C. In addition, FACT depletion results in the accumulation of cohesin within gene bodies that are not engaged in loop formation, which is associated with reduced transcription. Importantly, degradation of cohesin in FACT-depleted cells restores transcriptional output, indicating that cohesin mislocalisation underlies this effect. Together, these findings demonstrate that FACT facilitates cohesin translocation along chromatin, promoting efficient loop extrusion while preventing its aberrant accumulation within transcribed regions. This work provides mechanistic insight into how chromatin structure modulates cohesin function to coordinate genome organisation with transcription in mammalian cells.

biochemistry↗

bioRxiv2025

Neuronal migration induces DNA damage in developing brain

Migratory cells tend to have soft nuclei that deform and penetrate narrow spaces1,2. Extensive nuclear deformation during migration can cause nuclear envelope rupture and DNA damage in cancer cells, which may contribute to the malignant transformation during tumor progression3,4,5,6. However, the significance of DNA damage in physiological migration is less well understood. Here, we demonstrate that the migration of neurons in developing cerebral and cerebellar cortices is accompanied by massive DNA double-strand breaks (DSBs) due to mechanostress during passage through narrow interstitial spaces. Confined migration enhances the binding and cleavage of the genome by topoisomerase II{beta}, expressed in neuronal nucleus, independently of the nuclear envelope rupture. Genome sequencing revealed that DSBs tend to occur outside of protein-coding regions and transcription regulatory regions. During normal development, DSBs are rapidly repaired by the non-homologous end joining pathway. The deletion of ligase IV at the onset of neuronal migration leads to persistent DSB accumulation in cerebellar neurons with moderate transcriptional changes in genes related to synaptic function, neuronal development, and stress and immune responses. The mutant mouse develops mild motor deficits in later life, suggesting that the DNA damage generated during normal brain development poses a potential disease risk if left unrepaired.

cell biology↗

bioRxiv2020

Neuronal Enhancers are Hotspots For DNA Single-Strand Break Repair

Genome stability is essential for all cell types. However, defects in DNA repair frequently lead to neurodevelopmental and neurodegenerative diseases, underscoring the particular importance of DNA repair in long-lived post-mitotic neurons. The neuronal genome is subjected to a constant barrage of endogenous DNA damage due to high levels of oxidative metabolism in the central nervous system. Surprisingly, we know little about the identity of the lesion(s) that accumulate in neurons and whether they accrue throughout the genome or at specific loci. Here, we show that neurons, but not other post-mitotic cells, accumulate unexpectedly high numbers of DNA single-strand breaks (SSBs) at specific sites within the genome. These recurrent SSBs are found within enhancers, and trigger DNA repair through recruitment and activation of poly(ADP-ribose) polymerase-1 (PARP1) and XRCC1, the central SSB repair scaffold protein. Notably, deficiencies in PARP1, XRCC1, or DNA polymerase {beta} elevate the localized incorporation of nucleotides, suggesting that the ongoing DNA synthesis at neuronal enhancers involves both short-patch and long-patch SSB repair processes. These data reveal unexpected levels of localized and continuous DNA single-strand breakage in neurons, suggesting an explanation for the neurodegenerative phenotypes that occur in patients with defective SSB repair.

neuroscience↗