Male sterility and enhanced radiation sensitivity in TLS-/- mice

Abstract

TLS (also known as FUS) is an RNA-binding protein that contributes the N-terminal half of fusion oncoproteins implicated in the development of human liposarcomas and leukemias. Here we report that male mice homozygous for an induced mutation in TLS are sterile with a marked increase in the number of unpaired and mispaired chromosomal axes in pre-meiotic spermatocytes. Nuclear extracts from TLS(-/-) testes lack an activity capable of promoting pairing between homologous DNA sequences in vitro, and TLS(-/-) mice and embryonic fibroblasts exhibit increased sensitivity to ionizing irradiation. These results are consistent with a role for TLS in homologous DNA pairing and recombination.

The RNA-binding Protein Fused in Sarcoma (FUS) Functions Downstream of Poly(ADP-ribose) Polymerase (PARP) in Response to DNA Damage

“…Although other studies have implicated a role for FUS in maintaining resistance to genotoxic stress, possibly via participation in HR repair (34,40,41), the present results indicate that FUS functions are required for optimal DSB repair through both NHEJ and HR. FUS joins a growing list of RNA-processing factors including RBMX, PPM1G, THRAP3, hnRNPUL1 and -2, and NONO, that are recruited to the proximity of DSBs and whose activities are required for genotoxin resistance and DNA repair (51)(52)(53)(54).…”

“…Ϫ/Ϫ murine embryonic fibroblasts display increased chromosomal instability and radiosensitivity (40,41). Therefore, to address a biological requirement for human FUS in the response to DNA damage, we utilized a lentiviral system to stably express shRNA in U-2 OS cells against a NT control sequence, a coding sequence of FUS mRNA or the 3Ј-untranslated region.…”

“…FUS Ϫ/Ϫ mice exhibit defects in B lymphocyte development and activation, male sterility, chromosomal instability, and radiosensitivity, phenotypes that are closely aligned with DSB repair defects (40,41). Cellular extracts from FUS Ϫ/Ϫ testes are unable to promote pairing between homologous DNA sequences in vitro (41), and FUS was shown to promote D-loop formation (34), an essential step in the repair of DSBs through the HR pathway (42).…”

Multiple functional domains of the oncoproteins Spi-1/PU.1 and TLS are involved in their opposite splicing effects in erythroleukemic cells

“…TLS has been biochemically characterized as hPOMp75, a protein involved in homologous DNA pairing and recombination (Baechtold et al, 1999;Bertrand et al, 1999). This activity fits with the increased sensitivity to ionizing radiation due to chromosome pairing defects during meiosis in the TLS-deficient mice suggesting that TLS could participate to the maintenance of genomic integrity (Kuroda et al, 2000). Lastly, many data argue for a role of TLS in RNA processing.…”

Emerging roles of RNA and RNA-binding protein network in cancer cells

“…The RNA-binding RRM/RGG domain of TET family RBPs such as TLS/FUS (TransLocated in Sarcoma/FUsed in Sarcoma) and EWS (EWing Sarcoma) is frequently substituted by the DNA-binding domain of their fusion partner transcription factors (37). TET fusion proteins possess transforming potential that may be necessary and sufficient to confer oncogenicity (38)(39)(40)(41). However, the exact tumorigenic mechanism of TET fusion proteins awaits more study.…”