p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes

Abstract

Mice with a constitutive increase in p53 activity exhibited features of dyskeratosis congenita (DC), a bone marrow failure syndrome (BMFS) caused by defective telomere maintenance. Further studies confirmed, in humans and mice, that germline mutations affecting TP53 or its regulator MDM4 may cause short telomeres and alter hematopoiesis, but also revealed features of Diamond–Blackfan anemia (DBA) or Fanconi anemia (FA), two BMFSs, respectively, caused by defects in ribosomal function or DNA repair. p53 downregulates several genes mutated in DC, either by binding to promoter sequences (DKC1) or indirectly via the DREAM repressor complex (RTEL1, DCLRE1B), and the p53-DREAM pathway represses 22 additional telomere-related genes. Interestingly, mutations in any DC-causal gene will cause telomere dysfunction and subsequent p53 activation to further promote the repression of p53-DREAM targets. Similarly, ribosomal dysfunction and DNA lesions cause p53 activation, and p53-DREAM targets include the DBA-causal gene TSR2, at least 9 FA-causal genes, and 38 other genes affecting ribosomes or the FA pathway. Furthermore, patients with BMFSs may exhibit brain abnormalities, and p53-DREAM represses 16 genes mutated in microcephaly or cerebellar hypoplasia. In sum, positive feedback loops and the repertoire of p53-DREAM targets likely contribute to partial phenotypic overlaps between BMFSs of distinct molecular origins.

Ultrarare Variants in DNA Damage Repair Genes in Pediatric Acute-Onset Neuropsychiatric Syndrome or Acute Behavioral Regression in Neurodevelopmental Disorders

“…However, the fact that two different ultrarare variants were found in this gene in three cases from two families increases the likelihood they are playing a role. Interestingly, FC proteins interact with components of the p53 DDR pathway, including ATM and ATR (Figure 2) [122][123][124][125] . Some researchers have suggested that autoimmune and/or autoinflammatory processes underlie the development of behavioral regression in PANS and in a subgroup of individuals with ASD 35,[126][127][128] .…”

“…Interestingly, FC proteins interact with components of the p53 DDR pathway, including ATM and ATR (Figure 2) [126][127][128][129] . Some researchers have suggested that autoimmune and/or autoinflammatory processes underlie the development of behavioral regression in PANS and in a subgroup of individuals with ASD 34,[130][131][132] .…”