Biology subjects

Adam, S.

Publications and source records attributed to Adam, S..

2 recordsLinked to original sources

bioRxiv2018

The histone chaperones FACT and ANP32E reshape the chromatin landscape during DNA damage repair through H2A.Z/H2A.X histone variant exchange

Safeguarding cell function and identity following a genotoxic stress challenge entails a tight coordination of DNA damage signaling and repair with chromatin maintenance. How this coordination is achieved and with what impact on chromatin integrity remains elusive. Here, by investigating the mechanisms governing the distribution of H2A.X in mammalian chromatin, we demonstrate that this histone variant is deposited de novo at sites of DNA damage in a repair synthesis-coupled manner. Our mechanistic studies further identify the histone chaperone FACT (Facilitates Chromatin Transcription) as responsible for the deposition of newly synthesized H2A.X. Functionally, FACT potentiates H2A.X-dependent signaling of DNA damage and, together with ANP32E (Acidic Nuclear Phosphoprotein 32 Family Member E), orchestrates a H2A.Z/H2A.X exchange reaction that reshapes the chromatin landscape at repair sites. We propose that this mechanism promotes chromatin accessibility and helps tailoring DNA damage signaling to repair progression.\n\nHIGHLIGHTSO_LIH2A.X, but not H2A.Z, is deposited de novo at sites of DNA damage repair\nC_LIO_LIFACT promotes new H2A.X deposition coupled to repair synthesis\nC_LIO_LIFACT and ANP32E chaperones orchestrate H2A.Z/H2A.X exchange in damaged chromatin\nC_LIO_LIFACT stimulates H2A.X-dependent signaling of DNA damage\nC_LI

molecular biology↗

bioRxiv2017

Diagnostic Yield And Treatment Impact Of Targeted Exome Sequencing In Early-Onset Epilepsy

BackgroundTo examine the impact on diagnosis, treatment and cost with early use of targeted whole-exome sequencing (WES) in early-onset epilepsy.\n\nMethodsWES was performed on 50 patients with early-onset epilepsy ([≤] 5 years) of unknown cause. Patients were classified as retrospective (epilepsy diagnosis > 6 months) or prospective (epilepsy diagnosis < 6 months). WES was performed on an Ion ProtonTM and variant reporting was restricted to the sequences of 565 known epilepsy genes. Diagnostic yield and time to diagnosis were calculated. An analysis of cost and impact on treatment was also performed.\n\nResultsA likely/definite diagnosis was made in 17/50 patients (34%) with immediate treatment implications in 8/17 (47%). A possible diagnosis was identified in 9 additional patients (18%) for whom supporting evidence is pending. Time from epilepsy onset to genetic diagnosis was faster when WES was performed early in the diagnostic process (mean: 143 days prospective versus 2,172 days retrospective). Costs of prior negative tests averaged $8,344 in the retrospective group, suggesting savings of up to $5,110 per patient.\n\nInterpretationThese results support the clinical utility and potential cost-effectiveness of using targeted WES early in the diagnostic workup of patients with unexplained early-onset epilepsy. The costs and clinical benefits are likely to continue to improve. Advances in precision medicine and further studies regarding impact on long-term clinical outcome will be important.

genetics↗