RT Journal Article
SR Electronic
T1 Loss of FAM111B protease mutated in hereditary fibrosing poikiloderma syndrome negatively regulates telomere length
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.01.22.525054
DO 10.1101/2023.01.22.525054
A1 Kliszczak, Maciej
A1 Moralli, Daniela
A1 Jankowska, Julia D.
A1 Bryjka, Paulina
A1 Meem, Lamia Subha
A1 Goncalves, Tomas
A1 Hester, Svenja S.
A1 Fisher, Roman
A1 Clynes, David
A1 Green, Catherine M.
YR 2023
UL http://biorxiv.org/content/early/2023/01/23/2023.01.22.525054.abstract
AB Hereditary fibrosing poikiloderma (HFP) is a rare human dominant negative disorder caused by mutations in the FAM111B gene that encodes a nuclear trypsin-like serine protease. HFP patients present with symptoms including skin abnormalities, tendon contractures, myopathy and lung fibrosis. We characterised the cellular roles of human FAM111B using U2OS and MCF7 cell lines and report here that the protease interacts with components of the nuclear pore complex. Loss of FAM111B expression resulted in abnormal nuclear shape and reduced telomeric DNA content suggesting that FAM111B protease is required for normal telomere length; we show that this function is independent of telomerase or recombination driven telomere extension. Even though FAM111B-deficient cells were proficient in DNA repair, they showed hallmarks of genomic instability such as increased levels of micronuclei and ultra-fine DNA bridges. Interestingly, FAM111B variants, including mutations that cause HFP, showed more frequent localisation to the nuclear lamina suggesting that accumulation of mutant FAM111B at the nuclear periphery may drive the disease pathology.Competing Interest StatementThe authors have declared no competing interest.