Biology subjects

Imtiaz, A.

Publications and source records attributed to Imtiaz, A..

4 recordsLinked to original sources

bioRxiv2026

Human-specific remodeling of an endogenous retrovirus shapes structural diversity at acrocentric nucleolar organizer regions

Human acrocentric short arms harbor K111, an endogenous retrovirus that became an integral component of nucleolar organizer region (NOR)-associated architecture across all five acrocentric chromosome types. Here we combine complete human and primate genomes, haplotype-resolved population assemblies and parent-offspring trios to reconstruct its evolution and transmission. Predominantly full-length ancestral elements underwent human-specific expansion and remodeling, generating recurrent mosaics and individual-specific multicopy configurations. Population structural variation is concentrated in surrounding satellite landscapes rather than within K111-derived sequences themselves. Trio-resolved genomes reveal direct parental transmission, single-parent remodeling and, crucially, maternal-paternal remodeling in distinct configurations: large reciprocal domains with contrasting parental affinities and de novo sequence exchange within an offspring locus. Raw long reads support both maternal-paternal configurations. K111-derived loci associate with nucleolin-positive compartments. Together, these findings establish K111 as an evolutionarily dynamic component and molecular record of acrocentric NOR architecture, revealing unrecognized remodeling and sequence generation across human generations.

genetics↗

bioRxiv2026

Centromeric α-satellite DNA is a hotspot of genotoxic damage, incomplete repair, and cytoplasmic mislocalization

Centromeric -satellite DNA constitutes a highly repetitive and structurally specialized component of the human genome, yet the mechanisms underlying its damage susceptibility and repair fidelity under genotoxic stress remain undefined. Here, we demonstrate that genotoxic stress preferentially targets active centromeres, generating DNA double-strand breaks (DSBs) within -satellite arrays. Using bleomycin as a defined genotoxic perturbation, we identify dynamic alterations in centromeric repeat content, manifesting as net copy number losses and gains across multiple chromosome-specific -satellite arrays following damage. Similar centromere-associated damage signatures are observed in fibroblasts from patients with limited cutaneous systemic sclerosis, indicating that these features extend beyond experimental systems. Centromeric DSBs engage ATM-dependent DNA damage signaling and are repaired predominantly through RAD51-associated homologous recombination; however, repair fails to fully restore centromeric integrity. This incomplete repair is associated with defects in kinetochore organization, chromosome missegregation, and the formation of micronuclei containing centromeric DNA. Notably, [~]30% of these structures retain CENP-B but lacks detectable CENP-A, indicating disruption of centromere chromatin organization. Centromeric chromatin is frequently mislocalized to the cytoplasm following nuclear envelope perturbation, where immunofluorescence analysis reveals proximity to MHC class II (HLA-DRB1). Together, these findings establish centromeric -satellite DNA as a vulnerability hotspot under genotoxic stress, with implications for chromosome instability and chromatin antigen exposure in fibrosis-associated autoimmunity.

genetics↗

bioRxiv2025

Centromere instability links genome damage to immune activation in systemic sclerosis

Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which genomic sources of instability and their immunological consequences remain poorly defined. We show that bleomycin, a widely used SSc fibrosis model, induces DNA double-strand breaks (DSBs) at active centromeres. Similar centromeric damage signatures were observed in fibroblasts from patients with limited cutaneous SSc, consistent with prior observations. Quantification of -satellite repeat content revealed dynamic changes in repeat abundance, consistent with deletions and insertions and incomplete restoration following damage. These breaks are repaired primarily ATM-dependent, RAD51-associated homologous recombination, but repair remains incomplete. Incomplete repair is associated with altered kinetochore assembly, chromosome missegregation, and increased formation of micronuclei and cytoplasmic chromatin enriched in centromere proteins. These fragments escape via nuclear envelope rupture and show spatial colocalization with MHC class II molecules. Together, these findings establish bleomycin-induced centromere damage as a tractable model to study active-centromere instability, its incomplete repair, and the resulting chromatin mislocalization in fibroblasts, with features relevant to systemic sclerosis.

genetics↗

bioRxiv2024

Chromatin regulator HELLS mediates SSB repair and responses to DNA alkylation damage.

The SNF2 family chromatin remodeler HELLS has emerged as an important regulator of cell proliferation, genome stability, and several cancer pathways. Significant upregulation of HELLS has been reported in 33 human cancer types. While HELLS has been implicated in DNA damage response, its function in DNA repair is poorly understood. Here we report a new regulatory link between HELLS and single-strand break (SSB) repair in cellular responses to DNA alkylation damage. We found that loss of HELLS impairs SSB repair, and selectively sensitizes cells to DNA alkylating agents and PARP inhibitors (PARPi). Furthermore, we found that HELLS is co-expressed with PARP1 in cancer cells, and its loss is synthetic lethal with homologous recombination deficiency (HRD). This work unveils new functions of HELLS in modulating SSB repair and responses to clinically relevant DNA alkylation damage, thus offering new insights into the potential therapeutic value of targeting HELLS in cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/629292v2_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@2bbd3eorg.highwire.dtl.DTLVardef@1956f14org.highwire.dtl.DTLVardef@1afcb7corg.highwire.dtl.DTLVardef@58504c_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗