DCLRE1B

DNA interstrand cross-links prevent strand separation, thereby physically blocking transcription, replication, and segregation of DNA. DCLRE1B is one of several evolutionarily conserved genes involved in repair of interstrand cross-links (Dronkert et al., 2000 [PubMed 10848582]).

Full Name

DNA Cross-Link Repair 1B

Function

5'-3' exonuclease that plays a central role in telomere maintenance and protection during S-phase. Participates in the protection of telomeres against non-homologous end-joining (NHEJ)-mediated repair, thereby ensuring that telomeres do not fuse. Plays a key role in telomeric loop (T loop) formation by being recruited by TERF2 at the leading end telomeres and by processing leading-end telomeres immediately after their replication via its exonuclease activity: generates 3' single-stranded overhang at the leading end telomeres avoiding blunt leading-end telomeres that are vulnerable to end-joining reactions and expose the telomere end in a manner that activates the DNA repair pathways. Together with TERF2, required to protect telomeres from replicative damage during replication by controlling the amount of DNA topoisomerase (TOP1, TOP2A and TOP2B) needed for telomere replication during fork passage and prevent aberrant telomere topology. Also involved in response to DNA damage: plays a role in response to DNA interstrand cross-links (ICLs) by facilitating double-strand break formation. In case of spindle stress, involved in prophase checkpoint.

Biological Process

Double-strand break repair via nonhomologous end joining Source: GO_Central
Interstrand cross-link repair Source: BHF-UCL
Mitotic cell cycle checkpoint Source: UniProtKB
Protection from non-homologous end joining at telomere Source: UniProtKB
Telomere capping Source: BHF-UCL
Telomere maintenance Source: UniProtKB
Telomere maintenance via telomere lengthening Source: BHF-UCL
Telomeric 3' overhang formation Source: UniProtKB
Telomeric loop formation Source: UniProtKB

Cellular Location

Nucleus; Centrosome; Telomere. Mainly localizes to telomeres, recruited via its interaction with TERF2. During mitosis, localizes to the centrosome.

Involvement in disease

Hoyeraal-Hreidarsson syndrome (HHS):
The gene represented in this entry may be involved in disease pathogenesis. An aberrant splice variant of DCLRE1B, designated Apollo-Delta, has been found in a patient with Hoyeraal-Hreidarsson syndrome (PubMed:20479256). Apollo-Delta hampers the proper replication of telomeres, leading to major telomeric dysfunction and cellular senescence, but maintains its DNA interstrand cross-link repair function in the whole genome. A clinically severe variant of dyskeratosis congenita that is characterized by multisystem involvement, early onset in utero, and often results in death in childhood. Affected individuals show intrauterine growth retardation, microcephaly, cerebellar hypoplasia, delayed development, and bone marrow failure resulting in immunodeficiency.

PTM

Ubiquitinated, leading to its degradation. Interaction with TERF2 protects it from ubiquitination.