DNA Double-Strand Breaks as Pathogenic Lesions in Neurological Disorders

Abstract

The damage and repair of DNA is a continuous process required to maintain genomic integrity. DNA double-strand breaks (DSBs) are the most lethal type of DNA damage and require timely repair by dedicated machinery. DSB repair is uniquely important to nondividing, post-mitotic cells of the central nervous system (CNS). These long-lived cells must rely on the intact genome for a lifetime while maintaining high metabolic activity. When these mechanisms fail, the loss of certain neuronal populations upset delicate neural networks required for higher cognition and disrupt vital motor functions. Mammalian cells engage with several different strategies to recognize and repair chromosomal DSBs based on the cellular context and cell cycle phase, including homologous recombination (HR)/homology-directed repair (HDR), microhomology-mediated end-joining (MMEJ), and the classic non-homologous end-joining (NHEJ). In addition to these repair pathways, a growing body of evidence has emphasized the importance of DNA damage response (DDR) signaling, and the involvement of heterogeneous nuclear ribonucleoprotein (hnRNP) family proteins in the repair of neuronal DSBs, many of which are linked to age-associated neurological disorders. In this review, we describe contemporary research characterizing the mechanistic roles of these non-canonical proteins in neuronal DSB repair, as well as their contributions to the etiopathogenesis of selected common neurological diseases.

Iron associated lipid peroxidation in Alzheimer’s disease is increased in lipid rafts with decreased ferroptosis suppressors, tested by chelation in mice

“…Genomic damage during AD involves iron-derived oxidants. Heme from microbleeds and microhemorrhages may contribute to oxidants via iron from heme degradation by heme oxygenases 81 . AD brains have 2-fold increased double-strand DNA breaks (DSB) in neurons and astrocytes 82 .…”

Targeting the hSSB1-INTS3 Interface: A Computational Screening Driven Approach to Identify Potential Modulators

“…DNA double-strand breaks (DSBs) are one of the most cytotoxic lesions caused by endogenous damaging events such as replication stress, reactive oxygen species, and exogenous agents such as ionizing radiation (IR) and chemical agents. − If not repaired or improperly repaired, the damaged DNA can cause abnormalities in cellular functions and disease progression. , The DSBs occurring in the G2 phase of the cell cycle are mainly repaired by the error-free, homologous recombination (HR)-mediated repair pathway. , The HR repair is initiated with 3′-end resection, generating single-stranded DNA (ssDNA) overhangs . In eukaryotic cells, the ssDNA binding protein (SSB) complexes, e.g., RPA, the sensor of single-stranded DNA complex 1 and 2 (SOSS1 and SOSS2), bind to ssDNA and participate in DNA replication, repair, and recombination processes. − Compared to RPA, the SOSS1 complex has a lower affinity for ssDNA binding .…”

“…DNA double-strand breaks (DSBs) are one of the most cytotoxic lesions caused by endogenous damaging events such as replication stress, reactive oxygen species, and exogenous agents such as ionizing radiation (IR) and chemical agents. 1 − 3 If not repaired or improperly repaired, the damaged DNA can cause abnormalities in cellular functions and disease progression. 4 , 5 The DSBs occurring in the G2 phase of the cell cycle are mainly repaired by the error-free, homologous recombination (HR)-mediated repair pathway.…”

Senescence of cortical neurons following persistent DNA double-strand breaks induces cerebrovascular lesions

“…Genome instability with increased DNA double strand breaks (DSBs) is detrimental to neurons of the brain and has been implicated in diverse neurodegenerative disorders (NDs) [1][2][3][4][5][6] . However, the etiology of NDs is multifaceted, the progressive decline in number and activity of neurons exhibits significant comorbidity with glial and cerebrovascular abnormalities [7][8][9][10] .…”