Table 2 Hereditary accelerated aging disorders characterized by heightened replication stress^a,b

Ataxia Telangiectasia

ATM²¹⁸

Cerebellar ataxia

Progressive neuromotor deterioration

Immunodeficiency

Atrophy and hyperpigmentation

Defective coupling of replication stress response to metabolic remodeling during cellular senescence²¹⁹

Impaired mobilization of signaling response to DSBs; for review, see²²⁰

In yeast, ATM supports replisome stability during replication stress²²¹

Bloom Syndrome

BLM²²²

Growth deficiency

Sun-sensitivity

High cancer risk

Abnormal immune responses

Reduced rate of DNA synthesis and fork movement^223,224

Abnormal profile of DNA replication intermediates²²⁵

Reduced replication fork progression after hydroxyurea exposure²²⁶

Hypersensitivity to hydroxyurea^227,228

Defective processing of late-replicating DNA intermediates²²⁹

Cockayne Syndrome

CSA²³⁰, CSB²³¹

Severe photosensitivity

Impairment of physical development

Progressive neurological degeneration

Cataracts

Hearing loss

Hypersensitivity to agents that induce replication stress; for review, see²³²

CSB-deficient cells exposed to hydroxyurea display slowed fork progression⁵¹

CSB regulates fork degradation in BRCA1- or BRCA2-deficient cells⁵¹

CSB-deficient cells are compromised in mitotic DNA synthesis²³³

Dyskeratosis Congenita, Hoyeraal-Hreidarsson Syndrome

DKC1, RTEL1, DCLRE1B, NHP2, NOP10, NPM1, PARN, RPA1, TERC, TERT, TINF2, WRAP53, CTC1

For review, see⁴²

Bone marrow failure

Oral leukoplakia

Reticular skin pigmentation

Abnormal nail formation

Generalized shortened telomeres in affected patients; for review, see^42,234,235

RTEL1-depleted cells accumulate R-loops at sites of active replication²³⁶

HHS-linked RTEL1 mutations cause replication defects in unstressed cells²³⁷

RPA suppresses G4 formation, allowing proper telomere maintenance²³⁸

STN1 facilitates concerted G- and C-strand synthesis to regulate telomere length²³⁹

TIN2 helps to prevent ATR signaling during telomere replication and repress sister telomere association²⁴⁰

CTC1 in CST complex aids in C-strand fill-in DNA synthesis; also, genome-wide role to restart stalled forks; for review, see²³⁴

Fanconi Anemia

FANC-A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q, R, S, T, U, V, W

For review, see³⁶

Progressive bone marrow failure

Abnormalities in digits and stature

Predisposition to cancer

Malformation of organs

FANCD2 depletion compromises resolution of under-replicated DNA in SETX-deficient cells¹²¹

FANCJ-deficient cells exposed to G4-stabilizing ligands display reduced replication rate; for review, see⁸⁶

FA-mutated cells exposed to DNA cross-linking drugs are deficient in replication restart by BIR pathway²⁴¹

FA-deficient cells display destabilized replication forks stressed by DNA damage; for review, see¹⁴⁹

Hutchinson-Gilford Syndrome

LMNA²⁴²

Loss of subcutaneous fat

Alopecia

Failure to thrive during infancy

Hearing, sight, and dental loss

Disproportionate facial features

Replication fork stalling and induction of an interferon-like response⁴⁵

Lmna-/- MEFS exhibit impaired telomere maintenance²⁴³

HGPS cells display telomere attrition²⁴⁴

Defective replication fork restart after hydroxyurea exposure²⁴⁵

RECON Syndrome

RECQL1⁶⁸

Skeletal and joint abnormalities

Photosensitivity

Progeroid appearance

Xeroderma

Reduced replication in presence of topoisomerase inhibitors⁶⁸

Reduced ability to restart forks stalled by methylmethanesulfonate or hydroxyurea⁶⁸

Ruijs-Aalfs Syndrome

SPRTN⁵³

Lipodystrophy

Muscular atrophy

Low body weight

Early onset hepatocellular carcinoma

Neoplasms

Reduced DNA replication rate in SPRTN-knockout cells²⁴⁶

SPRTN-knockout cells accumulate DSBs in S-phase²⁴⁶

SPRTN facilitates replication bypass of formaldehyde-induced DNA-protein cross-links⁵⁶

Seckel Syndrome

ATR²⁴⁷

Severe dwarfism

Craniofacial features

Microcephaly

Intellectual disability

Seckel patient cells display impaired DNA damage response²⁴⁷

ATR-Seckel model is characterized by replication stress and accelerated aging²⁴⁸

Chromosomal breakage at fragile sites in Seckel syndrome cells after aphidicolin exposure²⁴⁹

Warsaw Breakage Syndrome

DDX11²⁵⁰

Microcephaly

Pre- and post-natal growth retardation

Abnormal skin pigmentation

Cochlear anomalies; hearing loss

Reduced replication fork progression after hydroxyurea exposure⁵⁹

Impaired binding of cohesin to chromatin during S-phase²⁵¹

Reduced replication fork speed after G4 ligand exposure⁶²

Werner Syndrome

WRN²⁵²

Bilateral ocular cataracts

Greying and loss of hair

Scleroderma appearance of skin

Short stature

Pinched facial features

Prolonged S-phase and reduced initiation of DNA synthesis^253,254,255

Reduced replication fork progression and recovery after DNA damage or fork stalling^226,256

Defective telomere lagging strand DNA synthesis²⁴

Sensitivity of WRN-depleted cells to hydroxyurea²²⁸