What is LIG4 syndrome?

Background. DNA Ligase IV (LIG4) syndrome is a rare disease with few reports to date. Patients suffer from a broad spectrum of clinical features, including microcephaly, growth retardation, developmental delay, dysmorphic facial features, combined immunodeficiency, and malignancy predisposition.

What causes LIG4 syndrome?

LIG4 syndrome is caused by mutations in the LIG4 gene (13q22-q34). The resulting defect of DNA ligase IV, a component of the classical non-homologous end-joining (NHEJ) pathway, affects the major mechanism of DNA double-strand break repair.

What does LIG4 do in response to DNA breaks?

Haematopoietic stem cell aging. Accumulation of DNA damage leading to stem cell exhaustion is regarded as an important aspect of aging. Deficiency of lig4 in pluripotent stem cells impairs Non-homologous end joining (NHEJ) and results in accumulation of DNA double-strand breaks and enhanced apoptosis.

How does non homologous end joining work?

Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as “non-homologous” because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair, which requires a homologous sequence to guide repair.

Which enzymes are ligases?

Ligases are enzymes that are capable of catalyzing the reaction of joining two large molecules by establishing a new chemical bond, generally with concomitant hydrolysis of a small chemical group on one of the bulky molecules or simply linking of two compounds together (e.g., enzymes that catalyze joining of C–O, C–S.

What proteins are involved in non-homologous end joining?

Ku excises abasic sites near DSBs in vitro and this activity was highest when the abasic site was within a short 5′ overhang at the DSB end. The proteins implicated in resecting DNA ends for NHEJ include Artemis, WRN, and APLF.

What is an Proenzyme?

proenzyme. / (prəʊˈɛnzaɪm) / noun. the inactive form of an enzyme; zymogen.

What is the action of ligases?

DNA ligases play an essential role in maintaining genomic integrity by joining breaks in the phosphodiester backbone of DNA that occur during replication and recombination, and as a consequence of DNA damage and its repair.

Do LIG4 mutations cause Rs-SCID?

This study shows that LIG4mutations can give rise not only to the LIG4 syndrome, characterized by pancytopenia and neurological defects, but also to RS-SCID without neurological defects and pancytopenia (except for lymphopenia).

What is the pathophysiology of LIG4 syndrome?

LIG4 syndrome is characterized by pancytopaenia, developmental and growth delay. Hypomorphic mutations in DNA ligase IV have been found in LIG4 syndrome patients, all of which markedly impact upon the protein function. One of the five patients identified developed leukaemia and showed dramatic clinical radiosensitivity.

Why do LIG4 mice die prenatally?

LIG4and XRCC4knockout mice die prenatally because of apoptosis of postmitotic neurons (18, 22–24). The neuronal defect of LIG4- or XRCC4-deficient mice can be rescued by a homozygous mutation in TP53or ATM(25–27).

What is the pathophysiology of lig4y288c mutation?

the Lig4Y288C mutation leads to multiple defects in lymphocyte development and function, including impaired V(D)J recombination, peripheral lymphocyte survival and proliferation, and B cell class switch recombination