DNA damage and repair: underlying mechanisms leading to microcephaly

Abstract

DNA-damaging agents and endogenous DNA damage constantly harm genome integrity. Under genotoxic stress conditions, the DNA damage response (DDR) machinery is crucial in repairing lesions and preventing mutations in the basic structure of the DNA. Different repair pathways are implicated in the resolution of such lesions. For instance, the non-homologous DNA end joining and homologous recombination pathways are central cellular mechanisms by which eukaryotic cells maintain genome integrity. However, defects in these pathways are often associated with neurological disorders, indicating the pivotal role of DDR in normal brain development. Moreover, the brain is the most sensitive organ affected by DNA-damaging agents compared to other tissues during the prenatal period. The accumulation of lesions is believed to induce cell death, reduce proliferation and premature differentiation of neural stem and progenitor cells, and reduce brain size (microcephaly). Microcephaly is mainly caused by genetic mutations, especially genes encoding proteins involved in centrosomes and DNA repair pathways. However, it can also be induced by exposure to ionizing radiation and intrauterine infections such as the Zika virus. This review explains mammalian cortical development and the major DNA repair pathways that may lead to microcephaly when impaired. Next, we discuss the mechanisms and possible exposures leading to DNA damage and p53 hyperactivation culminating in microcephaly.

A human-specific, concerted repression of microcephaly genes contributes to radiation-induced growth defects in forebrain organoids

“…IR causes DNA damage which normally induces a DDR (8). To investigate the activation of radiation-induced DNA damage in forebrain organoids, immunostainings were conducted for phosphorylated histone H2AX (ɣH2AX) and p53-binding protein 1 (53BP1), which both localize to DNA double-strand breaks (DSBs).…”

“…Therefore, we analyzed gene expression profiles of the 30 known MCPH genes (6,8,9) in our organoids, both during their development and after irradiation. We found that the majority of MCPH-associated genes were significantly downregulated during organoid maturation, with the biggest changes occurring between D28 and D56 (Figure 6C).…”

“…Irradiation of forebrain organoids leads to the accumulation of DNA damage followed by a p53-dependent DNA damage response and premature neuronal differentiation IR causes DNA damage which normally induces a DDR (8). To investigate the activation of radiation-induced DNA damage in forebrain organoids, immunostainings were conducted for phosphorylated histone H2AX (ɣH2AX) and p53-binding protein 1 (53BP1), which both localize to DNA double-strand breaks (DSBs).…”

“…Microcephaly primary hereditary (MCPH), a non-syndromic genetic form of primary microcephaly, is the most well-characterized subtype, for which 30 genes have been identified as causative and further referred to as “MCPH genes” (6,7). These genes are involved in centrosome biogenesis and DNA repair pathways, with patients often displaying genomic instability due to DNA damage accumulation and radiosensitivity (8,9). This underscores the particular sensitivity of the developing brain to DNA damage, which is further illustrated by the fact that DNA repair deficiency syndromes often display microcephaly as one of the most prominent features (8,10).…”

“…These genes are involved in centrosome biogenesis and DNA repair pathways, with patients often displaying genomic instability due to DNA damage accumulation and radiosensitivity (8,9). This underscores the particular sensitivity of the developing brain to DNA damage, which is further illustrated by the fact that DNA repair deficiency syndromes often display microcephaly as one of the most prominent features (8,10). Also, environmental exposures that can lead to microcephaly are prenatal irradiation or Zika virus infections, both of which result in DNA damage accumulation in neural progenitors (NPCs) (11,12).…”