Biology subjects

Chaudhary, J.

Publications and source records attributed to Chaudhary, J..

3 recordsLinked to original sources

bioRxiv2024

The mitotic CIP2A-TOPBP1 axis facilitates mitotic pathway choice between MiDAS and MMEJ

Mitotic DNA double-strand breaks (DSBs) accumulate in response to replication stress or BRCA1/2 deficiency posing a significant threat to genome stability as repair by non-homologous end-joining (NHEJ) and homologous recombination (HR) is inactivated in mitosis. Mitotic cells instead rely on the mechanisms of microhomology mediated end-joining (MMEJ) and mitotic DNA synthesis (MiDAS). However, how these pathways are regulated in mitosis remains unknown. Here we reveal the CIP2A-TOPBP1 complex facilitates recruitment of SMX complex components to mitotic chromatin marked by CIP2A, through a CDK1-dependent interaction between TOPBP1 BRCT 1/2 and SLX4 phospho-threonine1260, that drives MiDAS. Furthermore, CIP2A promotes the recruitment of Pol{theta} to facilitate mitotic MMEJ. This defines a mechanistic framework for mitotic DSB repair, where simultaneous disruption of MiDAS and MMEJ pathways underpins the synthetic lethality observed in BRCA1/2-deficient cells following CIP2A depletion. These findings provide critical insights into mitotic DNA repair and highlights therapeutic opportunities in HR deficient tumours.

molecular biology↗

bioRxiv2022

Consensus genomic regions associated with multiple abiotic stress tolerance in wheat and implications for wheat breeding

In wheat, a meta-analysis was performed using previously identified QTLs associated with drought stress, heat stress, salinity stress, water-logging stress, pre-harvest sprouting, and aluminium stress which predicted a total of 134 meta-QTLs (MQTLs) that involved at least 28 consistent and stable MQTLs conferring tolerance to five or all six abiotic stresses under study. Seventy-six MQTLs out of the 132 physically anchored MQTLs were also verified with genome-wide association studies. Around 43% of MQTLs had genetic and physical confidence intervals of less than 1 cM and 5 Mb, respectively. Consequently, 539 genes were identified in some selected MQTLs providing tolerance to 5 or all 6 abiotic stresses. Comparative analysis of genes underlying MQTLs with four RNA-seq based transcriptomic datasets unravelled a total of 191 differentially expressed genes which also included at least 11 most promising candidate genes common among different datasets. The promoter analysis showed that the promoters of these genes include many stress responsiveness cis-regulatory elements, such as ARE, MBS, TC-rich repeats, As-1 element, STRE, LTR, WRE3, and WUN-motif among others. Further, some MQTLs also overlapped with as many as 34 known abiotic stress tolerance genes. In addition, numerous ortho-MQTLs among the wheat, maize, and rice genomes were discovered. These findings could help with fine mapping and gene cloning, as well as marker-assisted breeding for multiple abiotic stress tolerances in wheat.

bioinformatics↗

bioRxiv2018

Mutant Screen Reveals the Piccolo’s Control over Depression and Brain-Gonad Crosstalk

Successful sexual reproduction involves complex, genetically encoded interplay between animal physiology and behavior. The rat provides a highly fecund mammalian model for studying how the brain impacts reproduction. Here, we report a forward genetics screen in rats to identify genes that affect reproduction. A panel of 18 distinct rat strains harboring Sleeping Beauty gene trap mutations were analyzed for the ability to reproduce. As expected, our mutant screen identified genes where reproductive failure was connected to gametogenesis (Btrc, Pan3, Spaca6, Ube2k) and embryogenesis (Alk3, Exoc6b, Slc1a3, Tmx4, Zmynd8). In addition, we identified Ata13 (longevity) and Pclo (neuronal disorders), previously not associated with an inability to conceive. Neurologically, Pclo is known to regulate the size of presynaptic vesicle pools. Here, dominant traits in Pclo mutant rats caused epileptiform activity and affected genes supporting GABAergic synaptic transmission (Gabra6, Gabrg3). Recessive traits in Pclo mutant rats transmitted altered reproductive behavior, as homozygous Pclo mutant rats produced gametes but neither sex would mate with wildtype rats. Pclo mutant rat behavior was linked to endophenotypes signifying compromised brain-gonad crosstalk via disturbed GnRH signaling and allelic markers for major depressive disorder in humans (Grm5, Htr2a, Sorcs3, Negr1, Drd2). Thus, by rat genetics, we identified Pclo as a candidate presynaptic factor required for reproduction. Author SummaryPiccolo gene mutations have previously been identified in human cohorts diagnosed with behavioral syndromes that impact ones emotions, including depression and bipolar disorder. Although studies in human populations implicate changes to Piccolos DNA sequence to enhanced susceptibility for behavioral disorders, studies in mouse models have yet to link Piccolo mutations to altered behavior. Here, by a novel genetics approach, we report Piccolo mutation-dependent effects on reproductive behavior in rats, a finding that may turn out to be relevant to the behavioral effects that are associated with human Piccolo gene mutations. Thus, research aimed at understanding how Piccolo functions to regulate reproduction in rats could prove pivotal in our ability to understand neurological mechanisms that influence human emotions.

genetics↗