Germline genome protection: implications for gamete quality and germ cell tumorigenesis

Abstract

Background: Germ cells have a unique and critical role as the conduit for hereditary information and therefore employ multiple strategies to protect genomic integrity and avoid mutations. Unlike somatic cells, which often respond to DNA damage by arresting the cell cycle and conducting DNA repair, germ cells as well as long-lived pluripotent stem cells typically avoid the use of error-prone repair mechanisms and favor apoptosis, reducing the risk of genetic alterations. Testicular germ cell tumors, the most common cancers of young men, arise from pre-natal germ cells.

Objectives: To summarize the current understanding of DNA damage response mechanisms in pre-meiotic germ cells and to discuss how they impact both the origins of testicular germ cell tumors and their remarkable responsiveness to genotoxic chemotherapy.

Materials and methods: We conducted a review of literature gathered from PubMed regarding the DNA damage response properties of testicular germ cell tumors and the germ cells from which they arise, as well as the influence of these mechanisms on therapeutic responses by testicular germ cell tumors.

Results and discussion: This review provides a comprehensive evaluation of how the developmental origins of male germ cells and their inherent germ cell-like DNA damage response directly impact the development and therapeutic sensitivity of testicular germ cell tumors.

Conclusions: The DNA damage response of germ cells directly impacts the development and therapeutic sensitivity of testicular germ cell tumors. Recent advances in the study of primordial germ cells, post-natal mitotically dividing germ cells, and pluripotent stem cells will allow for new investigations into the initiation, progression, and treatment of testicular germ cell tumors.

Keywords: DNA damage response; DNA repair; apoptosis; chemoresistance; chemosensitivity; germ cell; testicular germ cell tumor.

Figure 1.. Comparison of responses to DNA damage in differentiated somatic cells versus germ cells, pluripotent stem cells, and TGCTs.

(A) In response to DNA damage, somatic cells are more likely than germ cells/ES cells/TGCTs to undergo cell cycle arrest and attempt DNA repair, including utilization of error-prone repair mechanisms such as nonhomologous end-joining (NHEJ). (B) Germ cells, pluripotent, stem cells, and TGCTs are predisposed to apoptosis in response to DNA damage and when DNA repair mechanisms are activated in these cells, error-free mechanisms such as homologous recombination (HR) are favored.

Figure 2.. The DDR as an early barrier to tumorigenesis in somatic cells but not male germ cells.

(A) In somatic tissues, oncogenic events lead to aberrant cell proliferation and formation of hyperplastic precursor lesions. The replication stress and DNA damage associated with hyperproliferation activates the DDR, triggering senescence or apoptosis and simultaneously creating selective pressure to mutate DDR genes. Subsequent escape from the DDR tumorigenesis barrier results in an advanced malignancy with DDR defects. (B) In TGCTs, there is no apparent early-stage DDR activation and therefore no selective pressure to mutate DDR genes. Thus, TGCTs retain an intact DDR which contributes to their high rate of curability.

Figure 3.. Molecular determinants of TGCT chemosensitivity and chemoresistance.

When TGCTs are treated with genotoxic chemotherapeutics, they acquire DNA damage but are somewhat limited in DNA repair capacity. This, along with a propensity to undergo apoptosis, results in tumor regression, accounting for the unique curability of these tumors. Chemoresistance is associated with loss of pluripotency, alterations in repair pathway utilization, and avoidance of apoptosis.