Maintaining genomic integrity is critical to avoid life-threatening disorders, such as premature aging, neurodegeneration and cancer. A multiprotein cascade operates at sites of DNA double-strand breaks (DSBs) to recognize, signal and repair damage. RNF168 (ring-finger nuclear factor) contributes to this emerging pathway of several E3 ubiquitin ligases that perform sequential ubiquitylations on damaged chromosomes, chromatin modifications essential for aggregation of repair complexes at the DSB sites. Here, we report the clinical and cellular phenotypes associated with a newly identified homozygous nonsense mutation in the RNF168 gene of a patient with a syndrome mimicking ataxia-telangiectasia. The mutation eliminated both of RNF168's ubiquitin-binding motifs, thus blocking progression of the ubiquitylation cascade and retention of repair proteins including tumor suppressors 53BP1 and BRCA1 at DSB sites, consistent with the observed defective DNA damage checkpoints/repair and pronounced radiosensitivity. Rapid screening for RNF168 pathway deficiency was achieved by scoring patients' lymphoblastoid cells for irradiation-induced nuclear foci containing 53BP1, a robust assay we propose for future diagnostic applications. The formation of radiation-induced DSB repair foci was rescued by ectopic expression of wild-type RNF168 in patient's cells, further causally linking the RNF168 mutation with the pathology. Clinically, this novel syndrome featured ataxia, telangiectasia, elevated alphafetoprotein, immunodeficiency, microcephaly and pulmonary failure and has implications for the differential diagnosis of autosomal recessive ataxias.
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http://dx.doi.org/10.1038/cdd.2011.18 | DOI Listing |
J Genet Eng Biotechnol
December 2024
Faculty of Applied Medical Science Al Ula branch, Department of Nursing, Taibah University, Kingdom of Saudi Arabia; Department of Nuclear Medicine and Radiobiology, University of Sherbrooke, Sherbrooke, Quebec, J1H 5N4, Canada; Laboratory of Biochemistry and Molecular Biology, Faculty of Sciences of Bizerte, Carthage University, Tunisia. Electronic address:
Unlabelled: It is beyond doubt that radiotherapy is extremely effective in treating a wide variety of cancers. The sensitivity of the surrounding normal tissues limits the amount of radiation administered to the tumor. There is an urgent need to develop a treatment that combines pharmacological treatment with ionizing radiation (IR) specifically designed to specifically target cancer cells while protecting the surrounding normal tissue, resulting in an increase in the efficacy of the cancer treatment.
View Article and Find Full Text PDFPLoS One
December 2024
Department of Biological Sciences, University of South Carolina, Columbia, South Carolina, United States of America.
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic condition characterized by features of accelerated aging, and individuals with HGPS seldom live beyond their mid-teens. The syndrome is commonly caused by a point mutation in the LMNA gene which codes for lamin A and its splice variant lamin C, components of the nuclear lamina. The mutation causing HGPS leads to production of a truncated, farnesylated form of lamin A referred to as "progerin.
View Article and Find Full Text PDFTrends Genet
November 2024
Department of Biology, Technion - Israel Institute of Technology, Haifa 3200003, Israel. Electronic address:
DNA double-strand break (DSB) induction leads to local transcriptional silencing at damage sites, raising the question: Why are RNA processing factors (RPFs), including splicing factors, rapidly recruited to these sites? Recent findings show that DSBs cluster in a chromatin compartment termed the 'D compartment', where DNA damage response (DDR) genes relocate and undergo transcriptional activation. Here, we propose two non-mutually exclusive models to elucidate the rationale behind the recruitment of RPFs to DSB sites. First, RPFs circulate through the D compartment to process transcripts of the relocated DDR genes.
View Article and Find Full Text PDFJ Immunother Cancer
November 2024
Laura and Isaac Perlmutter Cancer Center, New York University, New York, New York, USA.
Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds to the intermediate-affinity interleukin-2 receptor, preferentially activating CD8 T cells and natural killer cells, with minimal expansion of regulatory T cells, thereby mitigating the risk of toxicities associated with high-affinity interleukin-2 receptor activation. Clinical outcomes with nemvaleukin are unknown. ARTISTRY-1 investigated the safety, recommended phase 2 dose (RP2D), and antitumor activity of nemvaleukin in patients with advanced solid tumors.
View Article and Find Full Text PDFNat Commun
November 2024
Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, Basel, Switzerland.
Combinational therapies provoking cell death are of major interest in oncology. Combining TORC2 kinase inhibition with the radiomimetic drug Zeocin results in a rapid accumulation of double-strand breaks (DSB) in the budding yeast genome. This lethal Yeast Chromosome Shattering (YCS) requires conserved enzymes of base excision repair.
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