ABSTRACT
The SLX4 tumor suppressor is a scaffold that plays a pivotal role in several aspects of genome protection, including homologous recombination, interstrand DNA crosslink repair and the maintenance of common fragile sites and telomeres. Here, we unravel an unexpected direct interaction between SLX4 and the DNA helicase RTEL1, which, until now, were viewed as having independent and antagonistic functions. We identify cancer and Hoyeraal-Hreidarsson syndrome-associated mutations in SLX4 and RTEL1, respectively, that abolish SLX4-RTEL1 complex formation. We show that both proteins are recruited to nascent DNA, tightly co-localize with active RNA pol II, and that SLX4, in complex with RTEL1, promotes FANCD2/RNA pol II co-localization. Importantly, disrupting the SLX4-RTEL1 interaction leads to DNA replication defects in unstressed cells, which are rescued by inhibiting transcription. Our data demonstrate that SLX4 and RTEL1 interact to prevent replication-transcription conflicts and provide evidence that this is independent of the nuclease scaffold function of SLX4.
Subject(s)
DNA Helicases/metabolism , DNA Replication , Recombinases/metabolism , Transcription, Genetic , DNA Helicases/genetics , Dyskeratosis Congenita/genetics , Fanconi Anemia Complementation Group D2 Protein/genetics , Fanconi Anemia Complementation Group D2 Protein/metabolism , Fetal Growth Retardation/genetics , Germ-Line Mutation , HeLa Cells , Humans , Intellectual Disability/genetics , Microcephaly/genetics , Recombinases/geneticsABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
The antihypertensive effects and tolerance of a fixed low-dose combination of the angiotensin-converting enzyme (ACE) inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg) were studied in patients with mild and moderate arterial hypertension. The patients' mean age was 51.35 +/- 5.02 years. The antihypertensive effects were evaluated from the results of daily blood pressure monitoring following 12 weeks of therapy. It was found that low-dose combination of perindopril and the indapamide exerted a multidirectional corrective effect on the daily blood pressure (BP): it provided a significant optimal BP lowering during a day on a long-term basis and significantly diminished the baseline increased systolic and diastolic BP variability during a day.
